Mood Meds news Meddle Bones

Transcription

news
®
DECEMBER 2011
Mood Meds
PLUS
Meddle with Bones
Progesterone in Fibroids
Fertility after Cancer
Endocrinology Trivia
December 2011
Vol. 36
No. 12
contents
NEWS & INSIGHTS FOR THE ENDOCRINE COMMUNITY
WWW.ENDO-SOCIETY.ORG
Features
Departments
22
SSRIs to Lift Mood
Undermine Bone
32
Uncovering Fibroids’
Mysteries
4 ...............................................Viewpoint
7 .........................................Editor’s Page
8 .................................Trends & Insights
19 ......................................Smart Moves
40 .................................Research Briefs
41 ............................Spotlight on Policy
47............................Practice Resources
53 ...................................Trainee Corner
55 .................................. Society Update
55 .............................................Calendar
56 ..................................... In Memoriam
59 ......................................... Classifieds
61 ......................................Puzzler Page
COVER STORY
Depression needs to be treated, but
should physicians simultaneously
tend patients’ bones?
Unexplained uterine growths are in a
research spotlight and progesterone
seems to be the main culprit.
47
Purging Cancer but
Keeping Fertility
61
How Hard Can This Be?
Without trials, new treatments for
human disease cannot be approved.
The Endocrine Society is seeking to
improve trial participation.
pg. 32
A new oncofertility program is
helping physicians educate patients
about options to preserve their fertility despite cancer treatments.
Can you recall these bizarre
and fun facts linked to endocrinology?
pg. 47
Ambiguous Genitalia
Take a look at The Hormone
Foundation’s bilingual fact sheet
on Ambiguous Genitalia
(page 49, 50).
Scan this QR code with
your smartphone/mobile
device for Endocrine
News Online.
ENDOCRINE.%73sDECEMBER 2011
41
Advocacy to Boost
Clinical Trial Participation
pg. 22
3
V IEWPOINT
Weigh In—It’s Your Society!
Dear Colleagues:
Each year at ENDO, The Endocrine
Society presents awards totaling
nearly $600,000 to members and
non-members alike. From undergraduate students to scientists in established careers, the awards recognize
individuals from all constituencies:
basic researchers, clinical researchers, and clinical practitioners, both
Janet E. Hall, M.D.
domestic and international. The Call
for Nominations to put forward candidates for a number of
Society awards will begin in early January. I would like to
encourage you to nominate your peers, mentors, or mentees.
Laureate Awards
Representing the highest achievement in the field of endocrinology, the Laureate Awards are bestowed on individuals
whose accomplishments are unmatched in science, leadership,
education, clinical practice, and service. Award recipients are
selected by the Laureate Awards Committee from nominations
by the Society’s membership. The committee encourages all
voting members, including trainees with doctoral degrees, to
submit a nomination. Armed with an expansive list of qualified
candidates, the committee continues to recognize deserving
endocrinologists for their science, dedication, mentorship,
and leadership. (See page 55 for this year’s winners.)
Trainee Awards
4
The Society has invested heavily in awards and grants
that recognize the outstanding achievements of trainees
and early career professionals. In 2011, it provided awards to
nearly 400 trainees. In 2012, it will continue to offer a robust
portfolio of trainee and early career investigator awards aimed
at encouraging trainees’ continued growth and contributions
to the Society and the field. Trainees who are both first and
presenting authors of an ENDO 2012 abstract are eligible for
the numerous abstract and travel awards, including the Mara
E. Lieberman, Eugenia Rosemberg, and Endocrine Society Outstanding Abstract Awards. In addition, trainee authors of the
highest scoring abstracts selected for poster presentation will
be invited to participate in the Presidential Poster Competition.
The Society is pleased to continue offering travel grant support to trainees wishing to attend the ENDO Endocrine Trainee
Day Workshop. Trainees who receive the Endocrine Trainee Day
Travel Award also receive complimentary registration to attend
ENDO 2012. Other awards offered are the Early Investigators
Awards for early career investigators, International Endocrine
Scholars Awards for international trainees, the Minority Access
Program Summer Research Awards for undergraduate students
from underrepresented communities, the Medical Student
Achievement Awards, the Summer Research Fellowship Awards,
the Amgen Scholars Award, the Lilly Endocrine Scholars Award,
and the Endocrinology and Molecular Endocrinology Student
Author Awards. (See page 53 for more on these awards.)
Other Awards
The Delbert A. Fisher Research Scholar Award recipient is
recognized for scholarly work on the history of endocrinology.
The scholar will deliver the Clark T. Sawin Memorial History of
Endocrinology Lecture at ENDO and submit a summary article
to be considered for publication in Endocrine News. Finally,
practicing physicians may compete for travel support to ENDO
through the Harold Vigersky Practicing Physician Travel Award.
The details and application information for all Society
awards are on the Society’s Web site and elsewhere in this
and other issues of Endocrine News.
2012 Election: The Society Needs Your Vote!
This is your opportunity to participate in selecting the
Society’s future leadership. The ballot for the 2012 Election of Officers and Council will launch in early January
2012. I would like to encourage you to cast your vote and
to remind your colleagues to do the same. The Society depends on your participation, so please take a few minutes
to submit your vote!
The positions on the 2012 ballot are: President-Elect
(Basic Scientist); Vice President (Clinical Scientist); Secretary
Treasurer; Council (one Physician-in-Practice seat and one
At-Large Council seat).
I would like to take this opportunity to thank the Nominating Committee members for their thoughtful deliberations
in selecting an excellent slate of candidates.
In closing, my best wishes for a wonderful holiday and
a Happy New Year. If you have any comments or questions,
please contact me at [email protected]. Q
Sincerely,
Sincerely,
Janet E. Hall, M.D.
President
NEW LOW-DOSE
t4."--&31"5$)8*5)
20% LESS ACTIVE
INGREDIENT1,2*
tRELIABLE EFFICACY
:06&91&$51
tSTRONG
4"'&5:130'*-&1,2
*Compared to Androderm® 2.5 mg/5 mg
References: 1. Androderm® full Prescribing Information, Watson
Pharma, Inc. October 2011. 2. Data on file, Watson Laboratories, Inc.
Androderm® is an androgen indicated for replacement therapy in adult males for conditions associated with a deficiency or absence
of endogenous testosterone.
IMPORTANT SAFETY INFORMATION
Androderm® should not be used in men with carcinoma of the breast, known or suspected carcinoma of the prostate, or patients
with pre-existing cardiac, renal, or hepatic disease. Androderm® should also not be used in pregnant or breastfeeding women, as
testosterone may cause fetal harm. Patients with benign prostatic hyperplasia (BPH) should be monitored for worsening signs and
symptoms, and exposure of Androderm® to women or children should be avoided. Exogenous administration of testosterone may
lead to azoospermia, and sleep apnea may occur in those with risk factors. Patients should be monitored for prostate specific antigen
(PSA), liver function, lipid concentrations, hematocrit, and hemoglobin. In a clinical study of 36 patients treated with Androderm®,
skin irritation from the patch was the most common adverse event (pruritus at application site [17%]), followed by application site
vesicles (6%), and back pain (6%).
Please see brief summary of full Prescribing Information on the following page.
For more information
visit Androderm.com
© 2011, Watson Pharma, Inc., Parsippany, NJ 07054. All rights reserved. 07745 10/11
Table 2. Adverse Reactions Seen With the Use of ANDRODERM 2.5 mg/day, 5 mg/day, or 7.5 mg/day (> 3%)
Adverse Reaction
BRIEF SUMMARY
For full Prescribing Information, see package insert.
INDICATIONS AND USAGE
ANDRODERM is an androgen indicated for replacement therapy in adult males for conditions associated with a
deficiency or absence of endogenous testosterone.
tPrimary hypogonadism (congenital or acquired): testicular failure due to conditions such as
cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter Syndrome,
chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone
concentrations and gonadotropins (FSH, LH) above the normal range.
tHypogonadotropic hypogonadism (congenital or acquired): idiopathic gonadotropin or luteinizing
hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation.
These men have low testosterone serum concentrations but have gonadotropins in the normal or low range.
Important limitations of use – Safety and efficacy of ANDRODERM in males <18 years old have not been
established [see Use in Specific Populations].
CONTRAINDICATIONS
tANDRODERM is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the
prostate [see Warnings and Precautions].
tANDRODERM is contraindicated in women who are, or who may become pregnant, or who are breastfeeding.
ANDRODERM may cause fetal harm when administered to a pregnant woman. ANDRODERM may cause serious
adverse reactions in nursing infants. If a pregnant woman is exposed to ANDRODERM, she should be apprised of
the potential hazard to the fetus [see Use in Specific Populations].
WARNINGS AND PRECAUTIONS
Worsening of Benign Prostatic Hyperplasia and Potential Risk of Prostate Cancer
tMonitor patients with benign prostatic hyperplasia (BPH) for worsening of signs and symptoms of BPH.
tPatients treated with androgens may be at increased risk for prostate cancer. Evaluate patients for prostate cancer
prior to initiating treatment. It is appropriate to re-evaluate patients 3 to 6 months after initiation of treatment, and
then in accordance with prostate cancer screening practices [see Contraindications].
Polycythemia
Increases in hematocrit, reflective of increases in red blood cell mass, may require lowering or discontinuation of
testosterone. Check hematocrit prior to initiating testosterone treatment. It is appropriate to re-evaluate the hematocrit
3 to 6 months after starting testosterone treatment, and then monitor annually. Discontinue testosterone therapy if the
hematocrit becomes elevated. Testosterone therapy may be restarted when the hematocrit decreases to an acceptable
level. An increase in red blood cell mass may increase the risk of thromboembolic events.
Use in Women and Children
Women and children should not use ANDRODERM. Use in women and children has not been studied
with ANDRODERM.
Due to lack of controlled studies in women and potential virilizing effects, ANDRODERM is not indicated for use in
women and children [see Contraindications and Use in Specific Populations].
Potential for Adverse Effects on Spermatogenesis
At large doses of exogenous androgens, including ANDRODERM, spermatogenesis may be suppressed through
feedback inhibition of pituitary follicle-stimulating hormone (FSH) that could lead to adverse effects on semen
parameters including reduction of sperm count.
Hepatic Adverse Effects
Prolonged use of high doses of orally active 17-alpha-alkyl androgens (methyltestosterone) has been associated with
serious hepatic adverse effects (peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice). Peliosis
hepatis can be a life-threatening or fatal complication. Long-term therapy with intramuscular testosterone enanthate
has produced multiple hepatic adenomas. ANDRODERM is not known to cause these adverse effects.
Edema
Androgens, including ANDRODERM, may promote retention of sodium and water. Edema, with or without
congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease
[see Adverse Reactions].
Gynecomastia
Gynecomastia may develop and persist in patients being treated with androgens, including ANDRODERM, for
hypogonadism.
Sleep Apnea
The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some patients, especially those
with risk factors such as obesity and chronic lung disease.
Lipids
Changes in serum lipid profile may require dose adjustment or discontinuation of testosterone therapy.
Hypercalcemia
Androgens, including ANDRODERM, should be used with caution in cancer patients at risk of hypercalcemia (and
associated hypercalciuria). Regular monitoring of serum calcium concentrations is recommended in these patients.
Decreased Thyroxine-Binding Globulin
Androgens, including ANDRODERM, may decrease concentrations of thyroxine-binding globulins, resulting in
decreased total T4 serum concentration and increased resin uptake of T3 and T4. Free thyroid hormone concentration
remains unchanged and there is no clinical evidence of thyroid dysfunction.
ADVERSE REACTIONS
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the
rates observed in practice.
Table 1 shows the adverse reactions that were reported by > 3% of 36 hypogonadal men who were treated with
ANDRODERM 2 mg/day, 4 mg/day, or 6 mg/day for 28 days. Of note, all hypogonadal men studied had been stable
users of topical testosterone replacement products prior to the study and there was no washout period between
therapies. Furthermore, there was only one subject titrated to 6 mg/day and he withdrew from the study prematurely.
Table 1. Adverse Reactions Seen With the Use of ANDRODERM 2 mg/day, 4 mg/day, or 6 mg/day (> 3%)
Adverse Reaction
Overall
N = 36
%
Application site pruritus
17
Application site vesicles
6
Back pain
6
Other less common adverse reactions reported by < 3% of patients included: application site erythema, application
site exfoliation, chills, diarrhea, fatigue, gastroesophageal reflux disease, hemarthrosis, hematuria, headache,
polyuria, and prostatitis. The overall incidence of application site reactions of any kind was 28% (10 subjects with 13
adverse reactions).
No serious adverse reactions to ANDRODERM 2 mg/day and 4 mg/day were reported during the clinical trial.
Table 2 shows the adverse reactions that were reported in > 3% of 122 patients in clinical studies with ANDRODERM
dosage strengths of 2.5 mg/day, 5 mg/day, and 7.5 mg/day. The most common adverse reactions reported were
application site reactions. Transient mild to moderate erythema was observed at the site of application in the majority
of patients at some time during treatment. The overall incidence of application site reactions of any kind was 48%
(59 subjects with 107 adverse reactions).
Overall
N = 122
%
Application site pruritus
37
Application site blistering
12
Application site erythema
7
Application site vesicles
6
Prostate abnormalities
5
Headache
4
Contact dermatitis to system
4
Application site burning
3
Application site induration
3
Depression
3
The following reactions occurred in less than 3% of patients: rash, gastrointestinal bleeding, fatigue, body pain, pelvic
pain, hypertension, peripheral vascular disease, increased appetite, accelerated growth, anxiety, confusion, decreased
libido, paresthesia, thinking abnormalities, vertigo, acne, bullae at application site, mechanical irritation at application
site, rash at application site, contamination of application site, prostate carcinoma, dysuria, hematuria, impotence,
urinary incontinence, urinary tract infection, and testicular abnormalities.
DRUG INTERACTIONS
Insulin
Changes in insulin sensitivity or glycemic control may occur in patients treated with androgens. In diabetic patients,
the metabolic effects of androgens may decrease blood glucose and, therefore, insulin requirement.
Oral Anticoagulants
Changes in anticoagulant activity may be seen with androgens. More frequent monitoring of INR and prothrombin
time is recommended in patients taking anticoagulants, especially at the initiation and termination of androgen
therapy.
Corticosteroids
The concurrent use of testosterone with ACTH or corticosteroids may result in increased fluid retention and should be
monitored, particularly in patients with cardiac, renal or hepatic disease.
Triamcinolone
tThe topical administration of 0.1% triamcinolone cream to the skin under the central drug reservoir prior to the
application of the ANDRODERM system did not significantly alter transdermal absorption of testosterone; however,
the rate of complete adherence was lower.
tPretreatment with triamcinolone ointment formulation significantly reduced testosterone absorption from the
ANDRODERM system.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category X [see Contraindications] — ANDRODERM is contraindicated during pregnancy or in women
who may become pregnant. Testosterone is teratogenic and may cause fetal harm. Exposure of a female fetus to
androgens may result in varying degrees of virilization. If this drug is used during pregnancy, or if the patient
becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Nursing Mothers
Although it is not known how much testosterone transfers into human milk, ANDRODERM is contraindicated in
nursing women because of the potential for serious adverse reactions in nursing infants. Testosterone and other
androgens may adversely affect lactation [see Contraindications].
Pediatric Use
Safety and efficacy of ANDRODERM have not been established in males < 18 years of age. Improper use may result in
acceleration of bone age and premature closure of epiphyses.
Geriatric Use
There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing
ANDRODERM to determine whether efficacy in those over 65 years of age differs from younger patients.
Additionally, there are insufficient long-term safety data in geriatric patients utilizing ANDRODERM to assess a
potential incremental risk of cardiovascular disease and prostate cancer.
Renal Impairment
No studies were conducted in patients with renal impairment.
Hepatic Impairment
No studies were conducted in patients with hepatic impairment.
DRUG ABUSE AND DEPENDENCE
Controlled Substance
ANDRODERM contains testosterone, a Schedule III controlled substance under the Anabolic Steroids Control Act.
Abuse
Anabolic steroids, such as testosterone, are abused. Abuse is often associated with adverse physical and
psychological effects.
Dependence
Although drug dependence is not documented in individuals using therapeutic doses of anabolic steroids for
approved indications, dependence is observed in some individuals abusing high doses of anabolic steroids. In
general, anabolic steroid dependence is characterized by any three of the following:
tTaking more drug than intended
tContinued drug use despite medical and social problems
tSignificant time spent in obtaining adequate amounts of drug
tDesire for anabolic steroids when supplies of the drug are interrupted
tDifficulty in discontinuing use of the drug despite desires and attempts to do so
tExperience of withdrawal syndrome upon discontinuation of anabolic steroid use
OVERDOSAGE
No cases of overdose with ANDRODERM have been reported in clinical trials. There is one report of acute
overdosage by injection of testosterone enanthate: testosterone concentrations of up to 11,400 ng/dL were implicated
in a cerebrovascular accident. Treatment of overdosage would consist of discontinuation of ANDRODERM together
with appropriate symptomatic and supportive care.
For all medical inquiries contact:
Watson Medical Communications
Parsippany, NJ 07054
800-272-5525
Manufactured By:
Watson Laboratories, Inc.
Salt Lake City, UT 84108 USA
Distributed By:
Watson Pharma, Inc.
Parsippany, NJ 07054 USA
Rx Only
Revised: October 2011
F ROM
THE
E DITOR
Endocrine News® is a registered trademark
owned by The Endocrine Society.
Janet E. Hall, M.D.
Dear Readers,
President
[email protected]
As the northern hemisphere enters
its darkest month, many patients with
seasonal adjustment disorder, along with
otherwise depressed patients, seek help
from their physicians. Some might find
that their mood improves with selective
serotonin reuptake inhibitors, drugs that
boost serotonin levels in the brain, but
they might be inadvertently undermining
the quality and strength of their bones.
What should physicians do about this
side effect? A Tri-Point article by three
experts in the field explains the latest
research in this area (page 22).
Uterine fibroids can cause pain,
bleeding, and, even if not felt, infertility. Surgery has been the main
treatment to date, but researchers are
uncovering more about the culpability of excess progesterone and chronic
vitamin D deficiency, both of which
could be tackled pharmacologically.
(page 32).
The shock of a cancer diagnosis is
bad enough, but in young women hoping to bear children, the prospect of
ova-damaging radiation and chemotherapy can be devastating. Scientists
are coming up with successful fertilitypreserving technologies (page 47).
We at Endocrine News wish you a
pleasant completion of 2011 and we
welcome your continued readership
in 2012. Q
William F. Young, Jr., M.D.
President-Elect
[email protected]
Kelly Mayo, Ph.D.
Past-President
[email protected]
John C. Marshall, M.D., Ph.D.
Secretary-Treasurer
[email protected]
Scott Hunt
Executive Director & CEO
[email protected]
Eleanore Tapscott
Senior Director of Publications
[email protected]
Doug Byrnes
Director of Publications
Sincerely,
Cathy Kristiansen
Editor
Endocrine News
[email protected]
Cathy Kristiansen
Editor
[email protected]
Jacqueline Ruttimann
Staff Writer
[email protected]
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them and find related links (www.endo-society.org/endo_news).
www.cadmus.com
Are Men or Women Happier?
How do XY disorders affect later sex life? Researchers investigated
satisfaction with overall sex life in these patients—and the results may
surprise you.
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Small D in Obesity
Children who skip breakfast and drink sodas may be sliding
down the slippery slope to weight gain. Such habits are associated
with lower vitamin D levels and heavier weight than in children with
healthier habits.
Printing & Prepress
7
News, Notes, & Insights
Estradiol Protects
Lungs from Injury
³ Estrogens pop up in
many parts of the body
apart from their “classical”
home in the reproductive
tract; one less-obvious place
is the lungs, where the hor-
www.endo-society.org
mones are active in development, differentiation,
and protection.
To see whether estrogens’ lung protection
extends to acute injury, a
research team examined
how far 17`-estradiol (E2)
braced the lungs against
oxidative stress and acute
alveolar anoxia.
The researchers induced
two types of oxidative
stress by perfusing guinea
pig lungs with the herbicide paraquat and
rat lungs with the
excitotoxic glutamate agonist
N-methyl-Daspartate.
They found
that both
chemicals led
to significant
injury by several measures,
but infusing E2
into the pulmonary circulation
before the onset of injury
significantly attenuated
the damage in both cases.
E2 infusion also yielded
significant protection
when the researchers
induced alveolar anoxia in
rat lungs.
The researchers then
experimented with selective estrogen receptor
agonists in an attempt
to determine what type
of mechanism estrogens
used to exert their actions:
genomic (binding to receptors in the nucleus, which
takes hours) or nongenomic (binding to plasma
membrane receptors,
which takes seconds or
minutes). In the model of
acute anoxia, the agonists
were as protective as E2,
and the effects were mediated by rapid, nongenomic
mechanisms.
To further investigate the mechanisms by
which E2 exerts its salu-
Ovarian Function Resumes after POF
8
³ Failing . . . or merely fitful? Ovarian function is known to intermittently resume in premature ovarian
failure (POF), but doctors have been
unable to identify which patients are
most likely to experience a spontaneous recovery. POF affects about
1% of women younger than age 40.
Defined as hypogonadism from either
follicular dysfunction or depletion,
the condition is of particular concern
when patients wish to conceive.
To identify prognostic factors for
ovarian functional recovery, scientists
guided by Philippe Touraine, M.D.,
Ph.D., at Groupe Hospitalier Pitié
Salpêtrière in Paris, France, undertook
a 4-year study of 358 patients with
idiopathic POF, diagnosed between
ages 26 and 34 years. Screening
included assessment of relevant history data, pelvic ultrasounds, and
genetic karyotyping.
In their paper, pending publication in The Journal of Clinical Endocrinology & Metabolism,*
the researchers report that 25% of
patients resumed ovarian function or
conceived within 2 years. Predisposing factors included lower inhibin B
and follicle-stimulating hormone levels (relative to that of nonresumptive
patients), higher estradiol levels, and
follicles detectable on ultrasound.
Not predictive were anti-Müllerian
hormone levels and a history of auto-
tary effects, the scientists concentrated on one
potential pathway—vasoactive intestinal polypeptide (VIP), which has
been reported to protect
against acute lung injury
in a variety of models.
The researchers, led
by Sami I. Said, M.D., of
the State University of
New York at Stony Brook
and the Veterans Affairs
Medical Center, in Northport, N.Y., found that E2
increased VIP gene expression in the lung. In their
upcoming article in Endocrinology,* they conclude
that VIP is an important
mediator of estradiolinduced pulmonary protection. Q
* Hamidi SA, Dickman KG,
Berisha H, Said SI. 17`-estradiol
protects the lung against acute
injury: Possible mediation by
vasoactive intestinal polypeptide. Endocrinology, doi:10.1210/
en.2011-1631.
immunity. Clinical factors predicting
functional recovery included having secondary (vs. primary) amenorrhea, as well as an age 20 years
at diagnosis and a history of normal
puberty. Surprisingly, a family history of POF also increases the likelihood of functional recovery.
The researchers conclude that
identifying POF patients who might
resume ovarian function is now possible with a predictive model. Genetic
counseling as well as family planning would be appropriate for these
patients, they add. Q
* Bidet M, Bachelot A, Bissauge E, et al. Resumption of ovarian function and pregnancies in 358
patients with premature ovarian failure. J Clin
Endocrinol Metab, doi:10.1210/jc.2011-1038.
³ The hunt is on to determine
genetic causes of obesity, and one
target is the enzyme short-chain
3-hydroxyacyl-CoA dehydrogenase
(SCHAD). Scientists are aware that
SCHAD deficiency is the only disease in which a defective enzyme
involved in fatty acid `-oxidation
is associated with soaring insulin levels. Because obesity is also
characterized by hyperinsulinemia,
a link might exist between fatty
acid oxidation and insulin secretion.
Consequently, investigators decided
to look more closely at the enzyme
and its encoding gene, hadh.
Annette Schurmann, Ph.D., at the
German Institute of Human Nutrition, Potsdam-Rehbruecke, and her
colleagues compared hadh-knockout
Substance P
Implicated in Diabetes
³ P could stand for “poison” in individuals trying
to avoid developing diabetes. A new study illustrates
that substance P (SP), a
neuropeptide found in numerous cell types, including fat depots, increases
insulin resistance at the
adipocyte level in a manner that might contribute
to type 2 diabetes.
As evidence has accumulated that adipose tissue is a major endocrine
organ, many studies have
linked changes in adipocyte physiology and function with the development
of insulin resistance and
diabetes. So Charalabos
Pothoulakis, M.D., of the
David Geffen School of
Medicine at the University of California at Los
Angeles, and his research
group decided to take a
closer look at SP and its
mice and wild-type mice under highfat diet conditions. In their paper,
forthcoming in Endocrinology,* the
researchers report that hadh-knockout
animals had lower body weight and
adiposity and higher plasma insulin
than their wild-type counterparts.
The obesity-preventive effects
possibly stem from the excretion
of acylcarnitines in urine and the
higher body temperature also noted
in knockout mice, which suggest
both that these animals must consume more food to produce adequate
adenosine triphosphate (ATP) and
that SCHAD is involved in thermogenesis. In addition, knockout mice
exhibited lower fasting and postprandial plasma glucose levels, probably
due to combined inefficient catabo-
receptor, neurokinin-1.
The researchers used
Tac 1-deficient mice, which
lack SP, and assessed how
SP influenced weight gain
and glucose metabolism in
mice fed a high-fat diet.
Although the Tac 1-deficient rodents and their
wild-type littermates gained similar amounts of
weight, the mice
without SP had
lower glucose
and leptin lev-
lism and increased insulin levels,
factors further implicating SCHAD.
The researchers suggest that
future studies should aim to precisely identify the origin of the
hypoglycemia found in these knockout mice. Additional research could
involve measuring plasma insulin
and glucose in thermoneutral conditions as well as adjusting diet and
feeding to ensure that knockout and
control mouse cohorts produce similar ATP levels. The researchers anticipate that if glucose levels remain low
in knockout mice under such conditions, then increased insulin secretion must cause the hypoglycemia. Q
* Schulz N, Himmelbauer H, Rath M, et
al. Role of medium- and short-chain L3-hydroxyacyl-CoA dehydrogenase in the
regulation of body weight and thermogenesis.
Endocrinology, doi:10.1210/en.2011-1547.
els and higher adiponectin
levels. They also responded
better to insulin challenge
after the high-fat diet.
The researchers then
investigated SP’s impact on
the expression of molecules
that may contribute to
reduced glucose uptake in
isolated human
mesenteric,
omental, and
subcutaneous
preadipocytes.
They found that
SP treatment
activated the intracellular
kinases JNK and PKC e, as
well as serine phosphorylation of IRS-1. SP also
caused IRS-1 serine phosphorylation in mature
human subcutaneous adipocytes, confirming that it
influences the intracellular effectors of the insulin
pathway in mature human
adipocytes as well as in
human preadipocytes.
In an upcoming Endocrinology article,* the
researchers say their novel
results—showing the neuropeptide’s effects on
insulin signaling at the
systemic level and in adipocytes—warrant more
scrutiny to clarify SP’s
involvement in obesityassociated pathologies. Q
* Karagiannides I, Stavrakis
D, Bakirtzi K, et al. Role of
substance P in the regulation of
glucose metabolism via insulin
signaling–associated pathways.
Endocrinology, doi:10.1210/
en.2010-1345.
Enzyme’s Mischief in Obesity
9
How EDCs Stop the Biological Clock Early
³ Here’s another reason why women
should not dally too long before
conceiving: Exposure to endocrine-disrupting chemicals (EDCs) might cause
premature shutdown of the female reproductive system, research indicates.
Both genes and the environment
contribute to female reproductive
senescence, which involves a complex
interplay of the hypothalamic-pituitary-ovarian (HPO) axis. Andrea Gore,
Ph.D., at The University of Texas at
Austin, and Mehmet Uzumcu, Ph.D.,
at Rutgers University, N.J., organized
a research group to conduct a variety
of animal and molecular biology studies to tease apart how EDCs affect the
HPO axis.
For 12 days, pregnant Fischer rats
received daily injections of one of
four treatments: dimethylsulfoxide
(DMSO) as a control, estradiol ben-
zoate (EB), or the estrogenic endocrine disruptor methoxychlor (MXC)
at either 20 μg/kg/day or 100 mg/
kg/day. After the prenatally exposed
female pups reached 16–17 months
(middle-aged by rat standards),
they were constantly monitored for
reproductive senescence via vaginal
smears. The hypothalamus of these
aging rats underwent real-time PCR
of 48 targeted genes or pyrosequencing to assess DNA methylation.
Unlike the DMSO-treated rats,
both the EB and MXC rats experienced diminished estrous cycles. In
the EB and high-dose MXC groups,
which had few if any cycles by 13
months of age, 15 genes in the
hypothalamic preoptic area (POA)
showed doubled expression levels. In
the MXC rats, 2 POA genes in particular stood out: those for gonadotro-
Fructose’s
Inflammatory
Effects
10
³ Data continue to build
on the different
metabolic impact
of fructose and glucose, the two main
dietary sugars.
A research team
led by Kimber Stanhope, R.D., Ph.D., and
Peter Havel, D.V.M.,
Ph.D., at the University of California, Davis,
compared the effects
of consuming fructoseand glucose-sweetened
beverages on a number of pro-inflammatory
markers, including MCP-1,
PAI-1, E-selectin, ICAM,
CRP, and IL-6 in 31 older,
pin-releasing hormone stimulatory
neuropeptide kisspeptin (Kiss1) and
the estrogen _ receptor Esr1. Furthermore, the researchers investigated DNA methylation on the Esr1
promoter. Compared with controls,
the EB rats had higher methylation
of 3 CpG islands in the Esr1 promoter; in the MXC rats, methylation
patterns matched those in controls.
“By hastening senescence, EDCs
may eliminate the possibility of biological children for women who …
postpone childbirth for personal or
professional reasons,” the authors
write in their upcoming article in
Molecular Endocrinology.* Q
* Gore AC, Walker DM, Zama AM, Armenti
AE, Uzumcu M. Early life exposure to endocrine-disrupting chemicals causes lifelong
molecular reprogramming of the hypothalamus and premature reproductive aging. Mol
Endocrinol, doi:10.1210/me.2011-1210.
overweight/obese men and
women (ages 40–72 years,
with a body mass index
range of 25–35 kg/m2). The
glucose- or fructose-sweetened drinks provided 25%
of their energy requirement
for 10 weeks.
Previous data from Drs.
Stanhope and Havel's team
revealed that consuming
fructose-sweetened drinks
for 10 weeks led to three
other hallmarks of metabolic syndrome: dyslipidemia, diminished insulin
sensitivity, and an increase
of visceral adipose deposition. The investigators
measured these inflammatory markers in subjects’
blood samples at baseline
and during the last treatment week. The results of
their study will be published soon in The Journal
of Clinical Endocrinology
& Metabolism.*
Subjects who consumed
fructose-sweetened drinks
exhibited increased circulating levels of MCP-1, PAI1, and E-selectin, whereas
those drinking glucosesweetened beverages did
not. ICAM, CRP, and IL-6
levels did not change significantly in either group.
In summary, these
results “suggest the possibility that prolonged
consumption of fructose
may contribute to the
development of metabolic
syndrome via induction of
specific pro-inflammatory
(MCP-1 and E-selectin) and
pro-thrombotic (PAI-1)
mediators,” the researchers write. Q
* Cox CL, Stanhope KL, Schwarz
JM, et al. Circulating concentrations of monocyte chemoattractant protein-1, plasminogen
activator inhibitor-1, and soluble
leukocyte adhesion molecule-1
in overweight/obese men and
women consuming fructose- or
glucose-sweetened beverages for
10 weeks. J Clin Endocrinol Metab,
doi:10.1210/jc.2011-1050.
Mealtime insulin therapy
matters inside the body.
But it first needs to fit
your patient’s life.
Choose Humalog and the MiniMed Paradigm REAL-Time Revel Insulin Pump
®
™
For adult patients with type 1 diabetes ready to have a conversation about using an insulin pump
• Humalog® (100 units /mL) can be used in a Paradigm Revel
Insulin Pump1
Indication for Humalog
• Humalog is an insulin analog indicated to improve glycemic control
in adults and children with diabetes mellitus.
Select Safety Information for Humalog
Select Safety Information for Humalog, continued
• Humalog is contraindicated during episodes of hypoglycemia
and in patients who are hypersensitive to Humalog or any of
its excipients.
• Humalog should not be diluted or mixed when used in an external
insulin pump. Change Humalog in the reservoir at least every 7 days.
Change the infusion set and insertion site at least every 3 days.
• Closely monitor blood glucose in all patients treated with insulin.
Change insulin regimens cautiously.
• Adverse reactions associated with Humalog in patients receiving
continuous subcutaneous insulin infusion: In adult patients,
catheter occlusions (0.09/month), infusion-site reactions (2.6%).
In children and adolescents, infusion-site reactions (21%).
• Humalog should be given within 15 minutes before or immediately
after a meal.
• Hypoglycemia is the most common adverse effect of Humalog
therapy. The risk of hypoglycemia increases with tighter glycemic
control. Severe hypoglycemia may be life threatening and can cause
seizures or death.
Reference
1. Paradigm® REAL-Time Revel™ User Guide. Starting on Insulin.©2009 Medtronic MiniMed, Inc. 47.
Please see Important Safety Information on next page and
Brief Summary of Full Prescribing Information for Humalog
on following pages.
For more information about Humalog, please call Eli Lilly and Company
at 1-800-545-5979. For more information about Paradigm®
REAL-Time Revel™, please call Medtronic at 1-888-350-3245.
Important Safety Information for Humalog
Important Safety Information for Humalog, continued
Contraindications
• Humalog® is contraindicated during episodes of hypoglycemia
and in patients who are hypersensitive to Humalog or any of
its excipients.
Warnings and Precautions, continued
• Renal or Hepatic Impairment: Frequent glucose monitoring
and insulin dose reduction may be required in patients with
renal or hepatic impairment.
Warnings and Precautions
• Dose Adjustment and Monitoring: Closely monitor blood
glucose in all patients treated with insulin. Change insulin
regimens cautiously. Concomitant oral antidiabetic treatment
may need to be adjusted.
• Mixing of Insulins: Humalog for subcutaneous injection
should not be mixed with insulins other than NPH insulin.
If Humalog is mixed with NPH insulin, Humalog should be
drawn into the syringe first. Injection should occur
immediately after mixing.
The time course of action for Humalog may vary in different
individuals or at different times in the same individual and is
dependent on many conditions, including delivery site, local
blood supply, or local temperature. Patients who change their
level of physical activity or meal plan may require insulin
dose adjustment.
• Hypoglycemia: Hypoglycemia is the most common adverse
effect of Humalog. The risk of hypoglycemia increases with
tighter glycemic control. Educate patients to recognize and
manage hypoglycemia. Hypoglycemia can happen suddenly
and symptoms may vary for each person and may change
over time. Early warning symptoms of hypoglycemia may
be different or less pronounced under conditions such as
long-standing diabetes, diabetic nerve disease, use of
medications such as beta-blockers, or intensified diabetes
control. These situations may result in severe hypoglycemia
and possibly loss of consciousness prior to the patient’s
awareness of hypoglycemia. Severe hypoglycemia may be
life threatening and can cause seizures or death.
Use caution in patients with hypoglycemia unawareness
and who may be predisposed to hypoglycemia. The patient’s
ability to concentrate and react may be impaired as a result
of hypoglycemia. Rapid changes in serum glucose levels may
induce symptoms similar to hypoglycemia in persons with
diabetes, regardless of the glucose value.
Timing of hypoglycemia usually reflects the time-action
profile of administered insulins. Other factors such as
changes in food intake, injection site, exercise, and
concomitant medications may alter the risk of hypoglycemia.
• Allergic Reactions: Severe, life-threatening, generalized
allergy, including anaphylaxis, can occur with Humalog.
• Hypokalemia: Humalog can cause hypokalemia, which,
if untreated, may result in respiratory paralysis, ventricular
arrhythmia, and death. Use caution in patients who may
be at risk for hypokalemia (eg, patients using potassiumlowering medications or medications sensitive to serum
potassium concentrations).
9404314-011 ©Medtronic MiniMed, Inc. 2011. All rights reserved.
HI70557 0611 PRINTED IN USA ©Lilly USA, LLC 2011. All rights reserved.
• Subcutaneous Insulin Infusion Pump: Humalog should not
be diluted or mixed when used in an external insulin pump.
Change Humalog in the reservoir at least every 7 days.
Change the infusion set and insertion site at least every
3 days.
Malfunction of the insulin pump or infusion set or insulin
degradation can rapidly lead to hyperglycemia and ketosis.
Prompt correction of the cause of hyperglycemia or ketosis
is necessary. Interim subcutaneous injections with Humalog
may be required. Train patients using an insulin pump to
administer insulin by injection and to have alternate insulin
therapy available in case of pump failure.
• Drug Interactions: Some medications may alter glucose
metabolism, insulin requirements, and the risk for
hypoglycemia or hyperglycemia. Signs of hypoglycemia
may be reduced or absent in patients taking anti-adrenergic
drugs. Particularly close monitoring may be required.
Adverse Reactions
• Adverse reactions associated with Humalog include
hypoglycemia, hypokalemia, allergic reactions, injection-site
reactions, lipodystrophy, pruritus, rash, weight gain, and
peripheral edema.
Use in Specific Populations
• Pediatrics: Humalog has not been studied in children with
type 1 diabetes less than 3 years of age or in children
with type 2 diabetes.
Dosage and Administration
• Humalog should be given within 15 minutes before or
immediately after a meal.
Please see following pages for Brief Summary of
Full Prescribing Information for Humalog.
HI HCP ISI 08JUN2011
MiniMed Paradigm REAL-Time Revel Insulin Pump
Indications for Use
Pump
The Paradigm Revel insulin pump is indicated for the
continuous delivery of insulin, at set and variable rates, for the
management of diabetes mellitus in persons requiring insulin.
MiniMed Paradigm REAL-Time Revel Insulin Pump
Important Safety Information
Contraindications
Pump therapy is not recommended for people who are
unwilling or unable to perform a minimum of four blood glucose
tests per day and to maintain contact with their healthcare
professional. Successful insulin pump therapy requires
sufficient vision or hearing to allow recognition of the pump
signals and alarms.
Warnings
The pump is not suitable for use in the presence of a flammable
anaesthetic mixture with air, oxygen or nitrous oxide.
Standard Luer sets are not compatible with the Medtronic
MiniMed Paradigm pump. Medtronic Diabetes Paradigm
reservoirs and Paradigm-compatible infusion sets are
specifically designed for use with the pump.
Do not modify your Paradigm reservoir or Paradigmcompatible infusion set.
Do not put any other drugs/medications inside your reservoir
to use with this pump. Only insulin that has been prescribed
by your physician can be used in this pump.
Do not use pump cases that have a magnetic clasp.
Do not expose your insulin pump to MRI equipment or other
devices that generate very strong magnetic fields. The magnetic
fields in the immediate vicinity of these devices can damage the
part of the pump’s motor that regulates insulin delivery, possibly
resulting in over-delivery and severe hypoglycemia. Your pump
must be removed and kept outside the room during magnetic
resonance imaging (MRI) procedures.
If your pump is inadvertently exposed to a strong magnetic
field, discontinue use and contact our 24 Hour HelpLine for
further assistance.
Please visit http://www.medtronicdiabetes.com/about/
safety.html for complete safety information.
Humalog® is a registered trademark of Eli Lilly and Company
and is available by prescription only.
Paradigm® is a registered trademark of Medtronic MiniMed, Inc.
Revel™ is a trademark of Medtronic MiniMed, Inc.
The MiniMed Paradigm Revel Insulin Pump does not include optional
continuous glucose monitoring (CGM) technology available from
Medtronic Diabetes. For information on the MiniMed Paradigm Revel
Insulin Pump integrated with CGM, please contact your Medtronic
Diabetes representative.
Please see Important Safety Information for Humalog on
opposite page.
Humalog®
(insulin lispro injection [rDNA origin])
Brief Summary: Consult the package insert for complete prescribing
information.
HUMALOG is an insulin analog indicated to improve glycemic control in adults and
children with diabetes mellitus.
CONTRAINDICATIONS
HUMALOG is contraindicated:
• during episodes of hypoglycemia
• in patients who are hypersensitive to HUMALOG or to any of its excipients.
Dose Adjustment and Monitoring²Glucose monitoring is essential for patients
receiving insulin therapy. Changes to an insulin regimen should be made cautiously
and only under medical supervision. Changes in insulin strength, manufacturer, type, or
method of administration may result in the need for a change in insulin dose. Concomitant
oral antidiabetic treatment may need to be adjusted.
As with all insulin preparations, the time course of action for HUMALOG may vary in
different individuals or at different times in the same individual and is dependent on many
conditions, including the site of injection, local blood supply, or local temperature. Patients
who change their level of physical activity or meal plan may require adjustment of insulin
dosages.
Hypoglycemia²Hypoglycemia is the most common adverse effect associated with
insulins, including HUMALOG. The risk of hypoglycemia increases with tighter glycemic
control. Patients must be educated to recognize and manage hypoglycemia. Hypoglycemia
can happen suddenly and symptoms may be different for each person and may change
from time to time. Severe hypoglycemia can cause seizures and may be life-threatening
or cause death.
The timing of hypoglycemia usually reflects the time-action profile of the administered
insulin formulations. Other factors such as changes in food intake (e.g., amount of food or
timing of meals), injection site, exercise, and concomitant medications may also alter the
risk of hypoglycemia [see Drug Interactions].
As with all insulins, use caution in patients with hypoglycemia unawareness and in
patients who may be predisposed to hypoglycemia (e.g., the pediatric population and
patients who fast or have erratic food intake). The patient’s ability to concentrate and react
may be impaired as a result of hypoglycemia. This may present a risk in situations where
these abilities are especially important, such as driving or operating other machinery.
Rapid changes in serum glucose levels may induce symptoms similar to hypoglycemia
in persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such
as longstanding diabetes, diabetic nerve disease, use of medications such as betablockers [see Drug Interactions], or intensified diabetes control. These situations may
result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s
awareness of hypoglycemia.
Hypersensitivity and Allergic Reactions²Severe, life-threatening, generalized
allergy, including anaphylaxis, can occur with insulin products, including HUMALOG [see
Adverse Reactions].
Hypokalemia²All insulin products, including HUMALOG, cause a shift in potassium
from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated
hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Use
caution in patients who may be at risk for hypokalemia (e.g., patients using potassiumlowering medications, patients taking medications sensitive to serum potassium
concentrations).
Renal or Hepatic Impairment²Frequent glucose monitoring and insulin dose
reduction may be required in patients with renal or hepatic impairment.
Mixing of Insulins²HUMALOG for subcutaneous injection should not be mixed
with insulin preparations other than NPH insulin. If HUMALOG is mixed with NPH insulin,
HUMALOG should be drawn into the syringe first. Injection should occur immediately after
mixing.
Do not mix HUMALOG with other insulins for use in an external subcutaneous
infusion pump.
Subcutaneous Insulin Infusion Pumps²When used in an external insulin pump for
subcutaneous infusion, HUMALOG should not be diluted or mixed with any other insulin.
Change the HUMALOG in the reservoir at least every 7 days, change the infusion sets and
the infusion set insertion site at least every 3 days. HUMALOG should not be exposed to
temperatures greater than 98.6°F (37°C).
Malfunction of the insulin pump or infusion set or insulin degradation can rapidly
lead to hyperglycemia and ketosis. Prompt identification and correction of the cause of
hyperglycemia or ketosis is necessary. Interim subcutaneous injections with HUMALOG
may be required. Patients using continuous subcutaneous insulin infusion pump therapy
must be trained to administer insulin by injection and have alternate insulin therapy
available in case of pump failure [see Dosage and Administration and How Supplied/
Storage and Handling].
Drug Interactions²Some medications may alter insulin requirements and the risk
for hypoglycemia or hyperglycemia [see Drug Interactions].
ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
• Hypoglycemia [see Warnings and Precautions].
• Hypokalemia [see Warnings and Precautions].
Clinical Trial Experience²Because clinical trials are conducted under widely varying
designs, the adverse reaction rates reported in one clinical trial may not be easily
compared with those rates reported in another clinical trial, and may not reflect the rates
actually observed in clinical practice.
The frequencies of Treatment-Emergent Adverse Events during HUMALOG clinical trials
in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the
tables below.
Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes
Mellitus (adverse events with frequency ≥5%)
Events, n (%)
Lispro
Regular human
Total
(n=81)
insulin (n=86)
(n=167)
Flu syndrome
Pharyngitis
Rhinitis
Headache
Pain
Cough increased
Infection
Nausea
Accidental injury
Surgical procedure
Fever
Abdominal pain
Asthenia
Bronchitis
Diarrhea
Dysmenorrhea
Myalgia
Urinary tract
infection
28 (34.6)
27 (33.3)
20 (24.7)
24 (29.6)
16 (19.8)
14 (17.3)
11 (13.6)
5 (6.2)
7 (8.6)
5 (6.2)
5 (6.2)
6 (7.4)
6 (7.4)
6 (7.4)
7 (8.6)
5 (6.2)
6 (7.4)
5 (6.2)
28 (32.6)
29 (33.7)
25 (29.1)
19 (22.1)
14 (16.3)
15 (17.4)
18 (20.9)
13 (15.1)
10 (11.6)
12 (14.0)
10 (11.6)
7 (8.1)
7 (8.1)
6 (7.0)
5 (5.8)
6 (7.0)
5 (5.8)
4 (4.7)
56 (33.5)
56 (33.5)
45 (26.9)
43 (25.7)
30 (18.0)
29 (17.4)
29 (17.4)
18 (10.8)
17 (10.2)
17 (10.2)
15 (9.0)
13 (7.8)
13 (7.8)
12 (7.2)
12 (7.2)
11 (6.6)
11 (6.6)
9 (5.4)
Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes
Mellitus (adverse events with frequency ≥5%)
Events, n (%)
Lispro
Regular human
Total
(n=714)
insulin (n=709)
(n=1423)
Headache
Pain
Infection
Pharyngitis
Rhinitis
Flu syndrome
Surgical procedure
63 (11.6)
77 (10.8)
72 (10.1)
47 (6.6)
58 (8.1)
44 (6.2)
53 (7.4)
66 (9.3)
71 (10.0)
54 (7.6)
58 (8.2)
47 (6.6)
58 (8.2)
48 (6.8)
149 (10.5)
148 (10.4)
126 (8.9)
105 (7.4)
105 (7.4)
102 (7.2)
101 (7.1)
Insulin initiation and intensification of glucose control
Intensification or rapid improvement in glucose control has been associated with a
transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy,
and acute painful peripheral neuropathy. However, long-term glycemic control decreases
the risk of diabetic retinopathy and neuropathy.
Lipodystrophy
Long-term use of insulin, including HUMALOG, can cause lipodystrophy at the site of
repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening
of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin
absorption. Rotate insulin injection or infusion sites within the same region to reduce the
risk of lipodystrophy [see Dosage and Administration].
Weight gain
Weight gain can occur with insulin therapy, including HUMALOG, and has been
attributed to the anabolic effects of insulin and the decrease in glucosuria.
Peripheral Edema
Insulin, including HUMALOG, may cause sodium retention and edema, particularly if
previously poor metabolic control is improved by intensified insulin therapy.
Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII)
In a 12-week, randomized, crossover study in adult patients with type 1 diabetes
(n=39), the rates of catheter occlusions and infusion site reactions were similar for
HUMALOG and regular human insulin treated patients (see Table 3).
Table 3: Catheter Occlusions and Infusion Site Reactions
HUMALOG
Regular human insulin
(n=38)
(n=39)
Catheter occlusions/
0.09
0.10
month
Infusion site reactions
2.6% (1/38)
2.6% (1/39)
In a randomized, 16-week, open-label, parallel design study of children and adolescents
with type 1 diabetes, adverse event reports related to infusion-site reactions were similar
for insulin lispro and insulin aspart (21% of 100 patients versus 17% of 198 patients,
respectively). In both groups, the most frequently reported infusion site adverse events
were infusion site erythema and infusion site reaction.
Allergic Reactions
Local Allergy—As with any insulin therapy, patients taking HUMALOG may experience
redness, swelling, or itching at the site of the injection. These minor reactions usually
resolve in a few days to a few weeks, but in some occasions, may require discontinuation
of HUMALOG. In some instances, these reactions may be related to factors other than
insulin, such as irritants in a skin cleansing agent or poor injection technique.
Systemic Allergy—Severe, life-threatening, generalized allergy, including anaphylaxis,
may occur with any insulin, including HUMALOG. Generalized allergy to insulin may cause
whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or
diaphoresis.
In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients
receiving regular human insulin (n=2969) and 30 patients receiving HUMALOG (n=2944).
Localized reactions and generalized myalgias have been reported with injected
metacresol, which is an excipient in HUMALOG [see Contraindications].
Antibody Production
In large clinical trials with patients with type 1 (n=509) and type 2 (n=262) diabetes
mellitus, anti-insulin antibody (insulin lispro-specific antibodies, insulin-specific
antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both
regular human insulin and HUMALOG (including patients previously treated with human
insulin and naive patients). As expected, the largest increase in the antibody levels
occurred in patients new to insulin therapy. The antibody levels peaked by 12 months and
declined over the remaining years of the study. These antibodies do not appear to cause
deterioration in glycemic control or necessitate an increase in insulin dose. There was no
statistically significant relationship between the change in the total daily insulin dose and
the change in percent antibody binding for any of the antibody types.
Postmarketing Experience²The following additional adverse reactions have been
identified during post-approval use of HUMALOG. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.
Medication errors in which other insulins have been accidentally substituted for
HUMALOG have been identified during postapproval use.
DRUG INTERACTIONS
A number of drugs affect glucose metabolism and may require insulin dose adjustment
and particularly close monitoring. Following are some of the examples:
• Drugs That May Increase the Blood-Glucose-Lowering Effect of HUMALOG and
Susceptibility to Hypoglycemia: Oral antidiabetic agents, salicylates, sulfonamide
antibiotics, monoamine oxidase inhibitors, fluoxetine, pramlintide, disopyramide,
fibrates, propoxyphene, pentoxifylline, ACE inhibitors, angiotensin II receptor blocking
agents, and somatostatin analogs (e.g., octreotide).
• Drugs That May Reduce the Blood-Glucose-Lowering Effect of HUMALOG:
corticosteroids, isoniazid, niacin, estrogens, oral contraceptives, phenothiazines,
danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline),
somatropin, atypical antipsychotics, glucagon, protease inhibitors, and thyroid
hormones.
• Drugs That May Increase or Reduce the Blood-Glucose-Lowering Effect of
HUMALOG: beta-blockers, clonidine, lithium salts, and alcohol. Pentamidine may
cause hypoglycemia, which may sometimes be followed by hyperglycemia.
• Drugs That May Reduce the Signs of Hypoglycemia: beta-blockers, clonidine,
guanethidine, and reserpine.
Pregnancy²Pregnancy Category B. All pregnancies have a background risk of birth
defects, loss, or other adverse outcome regardless of drug exposure. This background risk
is increased in pregnancies complicated by hyperglycemia and may be decreased with
good metabolic control. It is essential for patients with diabetes or history of gestational
diabetes to maintain good metabolic control before conception and throughout pregnancy.
In patients with diabetes or gestational diabetes insulin requirements may decrease
during the first trimester, generally increase during the second and third trimesters, and
rapidly decline after delivery. Careful monitoring of glucose control is essential in these
patients. Therefore, female patients should be advised to tell their physicians if they intend
to become, or if they become pregnant while taking HUMALOG.
Although there are limited clinical studies of the use of HUMALOG in pregnancy,
published studies with human insulins suggest that optimizing overall glycemic control,
including postprandial control, before conception and during pregnancy improves fetal
outcome.
In a combined fertility and embryo-fetal development study, female rats were given
subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human
subcutaneous dose of 1 unit/kg/day, based on units/body surface area, respectively) from
2 weeks prior to cohabitation through Gestation Day 19. There were no adverse effects
on female fertility, implantation, or fetal viability and morphology. However, fetal growth
retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal
weight and an increased incidence of fetal runts/litter.
In an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1,
0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.24 times the human subcutaneous dose of
1 unit/kg/day, based on units/body surface area, respectively) were injected subcutaneously
on Gestation days 7 through 19. There were no adverse effects on fetal viability, weight,
and morphology at any dose.
Nursing Mothers²It is unknown whether insulin lispro is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
HUMALOG is administered to a nursing woman. Use of HUMALOG is compatible with
breastfeeding, but women with diabetes who are lactating may require adjustments of
their insulin doses.
Pediatric Use²HUMALOG is approved for use in children for subcutaneous daily
injections and for subcutaneous continuous infusion by external insulin pump. HUMALOG
has not been studied in pediatric patients younger than 3 years of age. HUMALOG has not
been studied in pediatric patients with type 2 diabetes.
As in adults, the dosage of HUMALOG must be individualized in pediatric patients based
on metabolic needs and results of frequent monitoring of blood glucose.
Geriatric Use²Of the total number of subjects (n=2834) in eight clinical studies
of HUMALOG, twelve percent (n=338) were 65 years of age or over. The majority of
these had type 2 diabetes. HbA1c values and hypoglycemia rates did not differ by age.
Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of
HUMALOG action have not been performed.
OVERDOSAGE
Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes
of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage,
meal patterns, or exercise may be needed. More severe episodes with coma, seizure,
or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or
concentrated intravenous glucose. Sustained carbohydrate intake and observation may be
necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia
must be corrected appropriately.
DOSAGE AND ADMINISTRATION
Dosage Considerations²When given subcutaneously, HUMALOG has a more rapid
onset of action and a shorter duration of action than regular human insulin.
The dosage of HUMALOG must be individualized. Blood glucose monitoring is essential
in all patients receiving insulin therapy.
The total daily insulin requirement may vary and is usually between 0.5 to 1 unit/kg/
day. Insulin requirements may be altered during stress, major illness, or with changes in
exercise, meal patterns, or coadministered drugs.
Subcutaneous Administration²HUMALOG should be given within 15 minutes before
a meal or immediately after a meal.
HUMALOG given by subcutaneous injection should generally be used in regimens with
an intermediate- or long-acting insulin.
HUMALOG administered by subcutaneous injection should be given in the abdominal
wall, thigh, upper arm, or buttocks. Injection sites should be rotated within the same region
(abdomen, thigh, upper arm, or buttocks) from one injection to the next to reduce the risk
of lipodystrophy [see Adverse Reactions].
Continuous Subcutaneous Infusion (Insulin Pump)²HUMALOG may be administered
by continuous subcutaneous infusion by an external insulin pump. Do not use diluted
or mixed insulins in external insulin pumps. Infusion sites should be rotated within the
same region to reduce the risk of lipodystrophy [see Adverse Reactions]. Change the
HUMALOG in the reservoir at least every 7 days, change the infusion sets and the infusion
set insertion site at least every 3 days.
The initial programming of the external insulin infusion pump should be based on the
total daily insulin dose of the previous regimen. Although there is significant variability
among patients, approximately 50% of the total dose is usually given as meal-related
boluses of HUMALOG and the remainder is given as a basal infusion. HUMALOG is
recommended for use in pump systems suitable for insulin infusion such as MiniMed,
Disetronic, and other equivalent pumps.
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
HUMALOG 100 units per mL (U-100) is available as:
10 mL vials
NDC 0002-7510-01 (VL-7510)
3 mL vials
NDC 0002-7510-17 (VL-7533)
5 x 3 mL cartridges1
NDC 0002-7516-59 (VL-7516)
5 x 3 mL prefilled pen
NDC 0002-8725-59 (HP-8725)
5 x 3 mL Humalog KwikPen (prefilled)
NDC 0002-8799-59 (HP-8799)
Storage
Do not use after the expiration date.
Unopened HUMALOG should be stored in a refrigerator (36° to 46°F [2° to 8°C]), but
not in the freezer. Do not use HUMALOG if it has been frozen. In-use HUMALOG vials,
cartridges, pens, and HUMALOG KwikPen® should be stored at room temperature, below
86°F (30°C) and must be used within 28 days or be discarded, even if they still contain
HUMALOG. Protect from direct heat and light. See table below:
In-Use (Opened)
Not In-Use
Not In-Use
Room Temperature,
(Unopened)
(Unopened) Room
(Below 86°F [30°C])
Refrigerated
Temperature (Below
86°F [30°C])
10 mL vial
28 days
Until expiration date 28 days, refrigerated/
room temperature.
3 mL vial
28 days
Until expiration date 28 days, refrigerated/
room temperature.
3 mL cartridge
28 days
Until expiration date
28 days, Do not
refrigerate.
3 mL prefilled pen
28 days
28 days, Do not
refrigerate.
3 mL Humalog
28 days
28 days, Do not
KwikPen (prefilled)
refrigerate.
Use in an External Insulin Pump—Change the HUMALOG in the reservoir at least every
7 days, change the infusion sets and the infusion set insertion site at least every 3 days
or after exposure to temperatures that exceed 98.6°F (37°C). A HUMALOG 3 mL cartridge
used in the D-Tron® pumps should be discarded after 7 days, even if it still contains
HUMALOG. However, as with other external insulin pumps, the infusion set should be
replaced and a new infusion set insertion site should be selected at least every 3 days.
Diluted HUMALOG for Subcutaneous Injection—Diluted HUMALOG may remain in
patient use for 28 days when stored at 41°F (5°C) and for 14 days when stored at 86°F
(30°C). Do not dilute HUMALOG contained in a cartridge or HUMALOG used in an external
insulin pump.
Preparation and Handling
Diluted HUMALOG for Subcutaneous Injection—HUMALOG may be diluted with Sterile
Diluent for HUMALOG for subcutaneous injection. Diluting one part HUMALOG to nine parts
diluent will yield a concentration one-tenth that of HUMALOG (equivalent to U-10). Diluting
one part HUMALOG to one part diluent will yield a concentration one-half that of HUMALOG
(equivalent to U-50).
PATIENT COUNSELING INFORMATION: See FDA-approved patient labeling and Patient
Counseling Information section of the Full Prescribing Information.
____________
1
3 mL cartridge is for use in Eli Lilly and Company's HumaPen® Memoir™ and
HumaPen® Luxura™ HD insulin delivery devices, Owen Mumford, Ltd.’s Autopen®
3-mL insulin delivery device and Disetronic D-TRON® and D-TRON® Plus pumps.
Autopen® is a registered trademark of Owen Mumford, Ltd.
Humalog®, Humalog® KwikPen™, HumaPen®, HumaPen® Memoir™, HumaPen®
Luxura™ and HumaPen® Luxura™ HD are trademarks of Eli Lilly and Company.
Disetronic®, D-Tron®, and D-Tronplus® are registered trademarks of Roche
Diagnostics GmbH.
MiniMed® are registered trademarks of MiniMed, Inc.
Other product and company names may be the trademarks of their respective owners.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
Copyright © 1996, 2011, Eli Lilly and Company. All rights reserved.
Additional information can be found at www.humalog.com.
HI HCP BS 26MAY2011 PV5533
³ Milk “does a body
good,” but the mechanics
of lactation remain outside
scientists’ grasp. In many
mammals, successful lactation requires two staples—
good lipid reserves and
integration between liver
and white adipose tissue.
Now, research has thrown
another ingredient into
the mix: fibroblast growth
factor-21 (FGF21).
Yves Boisclair, Ph.D.,
at Cornell University in
Ithaca, N.Y., and his colleagues tested dairy cows,
measuring plasma levels of
FGF21 as the animals transitioned from late pregnancy to early lactation.
In an article pending
for Endocrinology,* the
researchers report that in
normally lactating cows,
plasma FGF21, which was
undetectable in late pregnancy, rose to a crest level
on the day of parturition
and then plateaued at an
elevated level during the
energy-deficit stage of early
lactation. In late lactation, dairy cows that were
feed restricted for 14 days
showed similar increases in
FGF21, which suggests that
energy insufficiency causes
chronically elevated FGF21
in early lactation.
Further molecular studies undertaken by Dr. Boisclair’s team showed that
the liver—not adipose tissue, skeletal muscle, or
mammary glands—contributed to the rise in plasma
FGF21 in early lactation.
Furthermore, the co-expression of the co-receptor
`-Klotho suggested that
FGF21 primarily affected
liver and adipose tissues.
“These data suggest a
model whereby liver-derived
FGF21 regulates the utilization of lipid reserves during
lactation via focal actions
on liver and adipose tissue,” the authors conclude.
Extending their findings
to humans might be difficult—unlike mice, women
do not experience measurable changes in total
energy demand from late
pregnancy to lactation. Q
* Schoenberg KM, Giesy SL,
Harvatine KJ, et al. Plasma
FGF21 is elevated by the
intense lipid mobilization of
lactation. in press. Endocrinology,
doi:10.1210/en.2011-1425.
Does Protein Acid Raise Urinary Calcium?
³ Hypercalciuria holds a mystery
close to its chest. We know that
diets with excessive animal protein
produce high urinary calcium levels,
elevating the risk of kidney stones
and bone loss, but why this happens
is unknown. Researchers led by Naim
M. Maalouf, M.D., at The University
of Texas Southwestern Medical Center in Dallas, investigated whether
the acid load caused by high-protein
diets might be the culprit.
In their study, to be published in
The Journal of Clinical Endocrinology & Metabolism,* the researchers
measured urinary calcium excretion
in 11 volunteers through 4 phases of
fixed diets. Phases 1 and 3 were control diets; phases 2 and 4 included
60 g additional animal protein and
60 mEq of either potassium citrate
(KCitrate) or, as a control salt, potassium chloride.
On the high protein diet, the
researchers detected significant differences in acid load between the
KCitrate and control salt regimens,
with KCitrate lowering the acid load
of the high-protein diet to levels
matching those of the control diet.
Nevertheless, urinary calcium excretion levels over a 24-hour period
barely differed between the KCitrate
and control salt regimens.
Because sodium and calcium intake
did not change from the control diet
phases to the high-protein phases,
the study team concluded it was
“unlikely that the changes in urinary
calcium observed during the [highprotein] phases were due to dietary
factors other than protein intake.”
The researchers acknowledge that
their study was too short to include
analysis of measures such as bone
density. For now, hypercalciuria with
excessive intake of animal proteins
retains its mystery. Perhaps longerterm studies of wider demographics
will ferret out the truth, they suggest, but at least protein acid load
can be dropped from the list of suspect causes. Q
* Maalouf NM, Moe OW, Adams-Huet B,
Sakhaee K. Hypercalciuria associated with
high dietary protein intake is not due to
acid load. J Clin Endocrinol Metab, doi:10.1210/
jc.2011-1531.
Lactation Induces
Plasma FGF21
17
SphK1’s Role in Diabetic Nephropathy
³ Research focused on a particular signaling pathway could turn a
major complication of diabetes—nephropathy—into a relatively minor
occurrence. Affecting 30%–40% of
diabetes patients, diabetic nephropathy is characterized by the buildup
of extracellular matrix proteins,
including fibronectin.
One potential signaling pathway
behind elevated fibronectin expression is sphingosine kinase-1 (SphK1),
STAT
18
Mammography screening reduces
breast cancer deaths by
< 25%,
an enzyme active in numerous pathological processes such as inflammation, oncogenesis, and angiogenesis.
Heqing Huang, Ph.D., at Sun Yat-sen
University in Guangzhou, China, and
his team examined the SphK1 pathway in a series of in vivo studies of
streptozotocin-induced diabetic rat
models and in vitro studies of rat
glomerular mesangial cells (GMC)
exposed to high glucose levels. Their
results are described in an upcoming
article in Molecular Endocrinology.*
Both the diabetic rat kidneys and
the GMC revealed increased fibronectin levels, along with activation
of the SphK1 signaling pathway.
When GMC overexpressed SphK1,
fibronectin levels rose even further.
Conversely, when GMC was either
tion of healing
by stimulating
suggesting that other types of
formation of
screening would be useful.
granulation
tissue.
Source: Welch HG, Frankel BA. Likelihood that a woman with
As reported
screen-detected breast cancer has had her “life saved” by
in an abstract at
that screening. Arch Intern Med, published online October
the Interscience
24, 2011, as doi:10.1001/archinternmed.2011.476.
Conference on
Antimicrobial
Agents and Chemotherapy, Lawrence
Eron, M.D., at the UniverGood Side of Flies:
Diabetic Wound Healing sity of Hawaii in Honolulu,
and his team used maggot
debridement therapy (MDT)
³ Diabetes patients
to treat 27 diabetes patients
bugged by non-healing
with complicated limb
limb infections might have
wounds (e.g., abscesses,
an ally in the insect world
ulcers, osteomyelitis, ganthat could forestall ampugrene) that had been prestation: biosurgery using
ent from several months to
maggots (fly larvae).
5 years. Each wound underIn use since the 16th
went an average of 5 thercentury, maggot therapy
apy cycles, with each cycle
promotes wound healentailing the application
ing via 3 mechanisms:
of 50–100 green blowfly
debridement of necrotic
and infected tissue without (Lucilia sericata) larvae and
their removal after 2 days.
damage to living healthy
The researchers defined suctissue, disinfection of the
cess as eradication of infecwound via the secretion of
tion, complete debridement
substances that inhibit or
of devitalized tissue, formakill bacteria, and accelera-
treated with a SphK1 inhibitor, N,Ndimethylsphingosine (DMS), or transfected with a small interfering RNA
against SphK1, fibronectin levels
dropped significantly. Adding DMS to
GMC also decreased transcription factor AP-1 expression; inhibiting AP-1
with curcumin attenuated fibronection expression in these cells.
The authors write that their
research highlights “a novel mechanism underlying the hyperglycemic
damage on the kidney and might
offer a new therapeutic strategy targeting [the] SphK1 pathway for the
prevention and treatment of diabetic
nephropathy.” Q
* Lan T, Liu W, Xie X, et al. Sphingosine
kinase-1 pathway mediates high glucoseinduced fibronectin expression in glomerular
mesangial cells. Mol Endocrinol, in press.
doi:10.1210/me.2011-0095.
tion of robust granulation
tissue, and > 75% closure of
wounds.
The treatment yielded a
78% success rate (21 of 27
patients). The researchers
attributed treatment failures to excessive inflammation surrounding the
wound, bleeding from the
wound, and fistulae from
infected bones that closed
after a single treatment.
MDT use is growing
throughout the world,
including in 300 U.S. and
1,000 European medical
centers. Although the “ick”
factor might be holding
back its popularity, its effi-
cacy in treating complex wounds in
diabetes patients and the
low price of larvae have
widened its use. An uninfected diabetic foot ulcer
can cost up to $10,000 to
treat and amputation costs
up to $65,000. In contrast,
200 medical-grade maggots
sell for about $100, so an
average 5-cycle treatment
would cost around $500. Q
* Eron L, Marineau M. Maggot debridement as salvage therapy for
complex diabetic limb wounds
that fail conventional antibiotic
therapy. Interscience Conference
on Anti-Microbial Agents and
Chemotherapy (ICAAC) 2011,
Abstract #L-697.
developments in the endocrinology world
* Sarah L. Berga, M.D., became professor and chair
of the Department of Obstetrics and Gynecology at
Wake Forest School of Medicine (WFSM) and vice
president for Women’s Health Services, a new role
within Wake Forest Baptist Health. Dr. Berga will also
be an associate dean at WFSM, focusing on research
and women’s health.
Robert G. Edwards, C.B.E., Ph.D., D.Sc., F.R.S.,
was knighted in the 2011 Queen’s Birthday Honours,
8 months after being awarded the Nobel Prize in
Physiology or Medicine “for the development of in
vitro fertilization.”
Keith Hruska M.D., is the new American Society for
Bone and Mineral Research president. He is professor
of pediatrics, medicine, and cell biology at Washington University and directs the Division of Pediatric
Nephrology at Washington University/St. Louis Children’s Hospital.
Bob Lowenberg, M.D., Ph.D., professor of hematology at Erasmus University Medical School, Rotterdam,
the Netherlands, in January 2013 will become editorin-chief of Blood, the official journal of the American
Society of Hematology.
Steve O’Rahilly, M.D., F.R.S., F.Med.Sci., was
elected a Foreign Associate of the National Academy
of Sciences in the U.S.A. Dr. O’Rahilly is professor of
clinical biochemistry and medicine at the University
of Cambridge, co-directs the Institute of Metabolic
Science, and is an honorary consultant physician at
Addenbrooke’s Hospital Cambridge.
* Abraham Thomas, M.D., M.P.H., head, Division of
Endocrinology, Diabetes, Bone and Mineral Disorders
and Whitehouse Chair in Endocrinology at Henry Ford
Hospital in Detroit, Mich., was appointed chair of the
Food and Drug Administration's Endocrinologic and
Metabolic Advisory Committee, through mid-2012.
*Member of The Endocrine Society
Share Your News
If you or others you know change jobs, receive a promotion,
are granted an award, or otherwise make endocrinologyrelated career news, please don’t hesitate to let us know at
[email protected].
³ While mothers need
their veggies, embryos need
VEGFs. Researchers say that
vascular endothelial growth
factor (VEGF) may play an
important—and hitherto
unnoted—role in embryo
implantation.
The endometrium is
receptive to blastocyst
implantation for only about
4 days each menstrual
cycle—in the mid-secretory
stage, when increased glandular secretions are thought
to prepare the endometrium to support an eventual pregnancy. Because
improved knowledge of the
makeup of these secretions
and their actions could
inform about fertility markers and the best conditions
for establishing pregnancy,
a group of researchers
looked at the growth factor
and cytokine profile of uterine fluid at different stages
of the menstrual cycle.
Natalie J. Hannan, Ph.D.,
of Prince Henry’s Institute
and the University of Melbourne in Australia, and
her colleagues analyzed
the uterine fluid in fertile
women during both the
nonreceptive and mid-proliferative cycle stages and
in women with unexplained
infertility during the midsecretory stage. They then
investigated how the fluid’s
components function vis-à-
vis implantation.
Analysis of uterine fluid
using quantitative immunoassays revealed the presence of more 30 cytokines,
chemokines, and growth
factors, 8 of which had not
been previously identified
in human uterine fluid.
The researchers then measured levels of these components at the different
menstrual cycle stages and
compared levels in fertile
vs. infertile women.
The team focused on
VEGF because its concentrations during the mid-secretory stage were significantly
lower in women with unexplained infertility than
in fertile women. Culturing mouse embryos with
either mid–secretory-stage
fluid from fertile women or
recombinant human VEGF
significantly enhanced blastocyst growth. Treatment
with either uterine fluid or
recombinant VEGF significantly increased endometrial
epithelial cell adhesion.
In an article pending
publication in Endocrinology,* the researchers say
their findings support the
concept that endometrial
secretions, particularly
VEGF, are key to successful
implantation. Q
* Hannan NJ, Paiva P, Meehan
KL, et al. Analysis of fertilityrelated soluble mediators in
human uterine fluid identifies
VEGF as a key regulator of embryo implantation. Endocrinology,
doi:10.1210/en.2011-1248.
SMART MOVES
Key Role for VEGF in
Implantation?
19
ACEI, angiotensin-converting enzyme inhibitor;
ARB, angiotensin receptor blocker;
BP, blood pressure; CO, cardiac output;
PVR, peripheral vascular resistance;
RAAS, renin-angiotensin-aldosterone system.
Not an actual health care professional.
For additional hypertension control,
– Renin triggers RAAS activation1
– Many untreated hypertensive
patients, including those with
diabetes, have an overactive RAAS4
– ACE inhibitors and ARBs only
partially block the RAAS1
References: 1. Jackson EK. Renin and angiotensin. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological Basis of
Therapeutics. 11th ed. New York, NY: McGraw-Hill Companies, Inc; 2006:789-822. 2. Data on file. Clinical study report 2327. Novartis Pharmaceuticals Corp.
3. Chrysant SG, Melino M, Karki S, Lee J, Heyrman R. The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure:
COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study. Clin Ther. 2008;30(4):587-604. 4. Alderman MH,
Cohen HW, Sealey JE, Laragh JH. Plasma renin activity levels in hypertensive persons: their wide range and lack of suppression in diabetic and in most
elderly patients. Am J Hypertens. 2004;17(1):1-7.
©2011 Novartis
6/11
XHV-1064621
COVER STORY
22
From The Endocrine Society’s Research Affairs Core Committee
Edited by Kerry Burnstein, Ph.D., and Cecilia Wang, M.D.
Introduction
Selective serotonin reuptake inhibitors
(SSRIs), drugs that uphold brain serotonin
levels, may ease the minds of patients
with depression and other psychiatric
disorders but have damaging side effects
on bone mineral density, raising the risk
of fracture. The mechanisms behind this
harm are not fully understood. In this TriPoint article, a clinical researcher, basic
scientist, and clinical practitioner sum up
the existing research.
BONE and Selective
Inhibitors
3 Perspectives
Serotonin Reuptake
23
CLINICAL RESEARCHER PERSPECTIVE
By Michael Bliziotes, M.D.
Dr. Bliziotes, is a staff physician at Portland Veterans Affairs
Medical Center, and professor of
medicine, Division of Endocrinology, Diabetes, and Clinical Nutrition, at Oregon Health and Science
University in Portland.
Highlights
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SSRI Use–Bone Health Relationship:
Clinical Evidence
24
SSRIs are a class of medications that selectively and
potently block the serotonin transporter (5-HTT). They are
widely used to treat major depressive disorder and several
other psychiatric conditions. Several studies in varied
populations have demonstrated an association of SSRI use
with bone mineral density (BMD). Cross-sectional studies
support this association in both men1, 2 and women.2, 3 More
important for showing causal associations, longitudinal
studies have shown that SSRI users have at least 1.6-fold
greater declines in BMD than those not taking SSRIs.3
An association between SSRIs and increased fracture
risk is supported by case-controlled studies using large,
administrative data sets from Denmark4 and Canada
(Manitoba 5 and Ontario 6). However, database studies
can be problematic because of the inability to control
for unmeasured variables (e.g., depressive symptoms).
Among several prospective cohort studies, higher
fracture rates were significant in men who used SSRIs
(Osteoporotic Fractures in Men [MrOS] cohort),7 older
men and women taking SSRIs (Canadian Multicentre
Osteoporosis Study [CaMOS] cohort),2 and SSRI-using
Dutch men and women 55 years and older. 8 In the
Women’s Health Initiative, SSRIs were associated with
increased risk of most fractures and wrist fractures but
not hip or clinical spine fractures.9 Thus, associations
between SSRIs and bone density, bone loss, or fractures
have been shown in several distinct populations, using
various study designs.
A few studies have examined SSRI dose and fracture
risk, with varied results. One demonstrated that SSRIs
were associated with a significant increase in the relative risk of hip fracture across doses.4 Another revealed
a dose effect for SSRIs using the Manitoba data set.5
The CaMOS study observed a dose-dependent effect for
SSRIs: 1.5-fold increase in risk of fragility fracture for
each unit increase in the daily dose of SSRI.2 The duration of SSRI use has also been associated with higher
fracture risk in some studies.2, 8, 10
Current Studies on SSRI’s Bone Impact:
Limitations
Several methodological problems inherent to epidemiologic studies complicate the interpretation of SSRI data
in terms of causality. One is confounding by indication,
which can exist if a disease and the treatment both have
potential to be associated with the outcome of interest.
In this case, depression has also been associated with
low bone density, falls, and fractures in some studies.
Within a particular study, it can be difficult to determine
whether the disease state (depression) or the treatment
(SSRIs) is responsible for the effects seen.
Depression and SSRIs have the potential to impact
bone through distinct or overlapping mechanistic pathways. For instance, SSRIs could influence bone through
reduced bone formation, increased bone resorption,
both, or through falls. The skeletal response to SSRIs
could be modulated by genetic differences in 5-HTT.
Depression could influence bone through inflammation,
physical inactivity, falls, decreased outdoor exposure
(and therefore lower vitamin D levels), hypercortisolism,
or hypogonadism. Theoretically, when a person has
persistent depressive symptoms and is taking an SSRI,
he/she could be at higher risk based on overlapping
pathways. Those with depressive symptoms that are in
remission after treatment with an SSRI and those using
SSRIs for non-depressive illness may be at lower risk.
Screening and Population Health: Implications
The evidence now seems sufficient to consider adding SSRIs to the list of medications that contribute to
osteoporosis. If added, clinicians should consider bone
density testing for patients on SSRIs, or those on SSRIs
with certain additional risk factors, to assess their
likelihood of fracture. At the least, it seems appropriate to expect that everyone taking SSRIs discuss bone
health with their providers. It is too early to suggest
that all SSRI users have BMD measures in the absence of
other risk factors, but the question could be answered
by trials comparing routine BMD testing with usual
care (i.e., measuring/supplementing vitamin D, calcium
supplementation, exercise) using fracture outcomes.
Mounting evidence supports serotonin as an important regulatory agent in bone. Further work is required
to establish the full skeletal effects of the clinically
popular SSRIs, which inhibit the 5-HTT and are used for
the management of major depressive disorder and other
affective conditions. Resolution of remaining questions
about SSRIs and their contribution to bone loss, falls
(perhaps related to depression per se), and fractures will
require randomized, controlled trials with careful assessment of depression and depressive symptoms.
BASIC RESEARCHER PERSPECTIVE
By Gerard Karsenty, M.D., Ph.D.
Dr. Karsenty is professor and
chair of genetics and development
at Columbia University in New
York City.
Highlights
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The clinical observation that SSRI use is associated
with bone loss initially puzzled us, mainly because we did
not know much about serotonin. On reading and learning
more, mostly from patients using SSRIs, we realized that
here was a biological problem worth studying.1–3 In more
ways than one, our ignorance of the field greatly helped
us by preventing any preconceived ideas from interfering with our scientific investigation. What started as an
investigation of the function of brain-derived serotonin
in regulating bone mass accrual expanded unexpectedly
to include the regulation of appetite, the definition of the
roadmap of leptin signaling in the brain, and eventually
the molecular elucidation of two human genetic diseases.4–6
Our hypothesis stated that the deleterious effect of
SSRIs on bone health simply meant that brain-derived
serotonin, in ways that needed to be defined, influences
bone mass accrual. The fact that serotonin does not cross
the blood-brain barrier was quite important in our eyes.7 It
implied that if we could show that brain-derived serotonin
regulates bone mass, it would be the first demonstration
that bona fide neuromediators(s) regulate(s) bone mass
accrual. To this end, my laboratory generated mice lacking tryptophan hydroxylase 2 (Tph2)—the rate-limiting
initial enzyme in brain-derived serotonin biosynthesis.4
Expression of the gene coding for this enzyme could be
detected only in neurons of the brainstem.4 The importance
of this experiment derived from the use of a “straight” gene
deletion mouse model without the uncertainties that can
be invoked in cell-specific gene deletion mouse models.
After verifying that serotonin was virtually absent from
the brain but normally present in the general circulation,
we asked how its absence affected bone mass accrual or, by
inference, what the function of brain-derived serotonin was
in this context. Mutant mice unable to synthesize serotonin
in the brain were severely osteoporotic. In other words,
brain-derived serotonin favors bone mass accrual by increasing bone formation and decreasing bone resorption.4 These
mutant mice had a second obvious phenotype: They were
anorectic.4 This meant that, as is the case in invertebrates,
brain-derived serotonin enhances appetite in vertebrates.
The conjunction of low bone mass and anorexia struck us
because it is the mirror image of what is observed when
leptin is absent. What was even more troubling is that the
known mediators of leptin regulation of bone mass accrual
and appetite were also regulated by brain-derived serotonin—but in opposite ways. These striking coincidences
implied that leptin could inhibit appetite and bone mass
accrual by acting in serotonergic neurons of the brainstem.
This finding allowed us to return to what started this project:
that SSRIs affect appetite and bone mass accrual because
they disrupt leptin signaling in the brain. Eight different
lines of evidence indicate that this is the case:
1. Functional leptin receptors are present on serotonergic
neurons of the brainstem.
2. Treatment of wild-type mice with leptin produces a dosedependent decrease in brain-derived serotonin synthesis.
3. Conversely, serotonin content is abnormally high in
the brains of leptin-deficient mice.
4. Electrophysiological studies demonstrated that leptin
also inhibited the release of serotonin made in brainstem
neurons.
5. Axon guidance experiments showed that serotonin
made in brainstem neurons could reach neurons of the
ventromedial and arcuate hypothalamic nuclei, bind
to distinct receptors on each of these two nuclei, and
elicit in both cases a CREB-dependent signaling cascade
affecting bone mass accrual and appetite, respectively.4–6
6. Normalizing serotonin context in the brain of ob/ob
mice by removing one allele of Tph2 normalized their
appetite and bone mass, whereas removing both copies
of Tph2 made them anorectic. The power of this experiment stems from the fact that it does not involve any
cell-specific gene deletion.
7. That an inhibitor of one of the two serotonin receptors
located on arcuate neurons and mediating serotonin
inhibition of appetite could curb appetite in ob/ob mice
verified the biological importance of this pathway.
Conclusion
25
8. A genetic trick allowing inactivation of only Tph2 in
adult mice showed that these two functions of serotonin occurred not only during development but also
in adult mice.
In sum, what started as the biological investigation of the
side effects of a popular class of drugs led to the elucidation
of the leptin roadmap in the brain and to the realization that
this could be of importance from a therapeutic point of view.
If we go back now to the clinical observation that started
this project, this work implies that in SSRI-treated patients
developing bone loss and/or hyperphagia, there is likely
to be a defect in serotonin signaling in the hypothalamus.
case-controlled, and longitudinal studies have shown that
SSRI therapy is associated with both low BMD and increased
fracture risk.2–4 Depression is frequently associated with
detrimental health habits such as smoking, alcohol intake, poor nutrition, and sedentary lifestyle, which are all
recognized risk factors for decreased BMD and increased
fractures; thus SSRI use may add to these risk factors. In
addition, SSRIs are used as an alternative therapy for hot
flashes after menopause, which might further exacerbate the
deleterious effects of estrogen depletion on the skeleton.5
Consequently, the potential contribution of SSRI use to low
BMD and osteoporotic fractures is considerable.
Depression and SSRI Use: Skeletal Effects
CLINICAL PRACTITIONER PERSPECTIVE
By Shiri Levy, M.D.
Dr. Levy is senior staff physician, Henry Ford Hospital, Detroit,
Mich., and service chief, West
Bloomfield Henry Ford Hospital,
Division of Endocrinology, Diabetes, Bone and Mineral Disorders.
Highlights
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SSRIs and Osteoporosis: Scope of the Problem
26
Osteoporosis and osteoporotic fractures are major public
health problems with significant morbidity, mortality, and
health care expenditures. Although a vast majority (> 80%)
of fractures are related to estrogen deficiency in women
and hypogonadism in men, osteoporosis occurs in a substantial number of patients receiving drugs for a variety of
conditions.1 Drug-induced osteoporosis is most commonly
(> 90%) due to glucocorticoids. However, a growing number of drugs, including SSRIs, have been implicated in the
pathogenesis of osteoporotic fractures.1 Thus, even a small
fraction of individuals sustaining fractures as a result of
these drugs represents a significant health care problem.
Six million Americans aged 65 years and older suffer from
depression. The lifetime risk of clinical depression ranges
from 5%–12% in men and 10%–25% in women. SSRIs are
first-line therapies for depression. Several cross-sectional,
In many studies, depressive symptoms are associated
with bone loss and/or increased fractures.6, 7 In a casecontrolled study, after adjusting for age, depressed patients had 15% lower BMD than controls.8 The underlying
mechanism(s) for this association is (are) unknown, but
may be related to alterations in the hypothalamic-pituitary-adrenal and/or -gonadal axes. Depressed individuals
may be hypercortisolemic or have hypothalamic hypogonadism, both known to adversely affect the skeleton. Furthermore, cytokines and neuroendocrine hormones, which may
decrease bone formation or increase bone resorption, are
altered in the depressed state.9 For example, inflammatory
cytokines such as interleukin-6 and C-reactive protein are
elevated in depression and are associated with low BMD.10
Apart from these hormonal influences, depressed patients
often have difficulty maintaining healthy lifestyle behaviors, which has further negative impact on the skeleton.
Since the publication of exciting reports on “brain-bone”
connections, the association between SSRI use and osteoporosis has received much attention.2 SSRIs block serotonin
transporters expressed in osteoblasts and osteocytes. In the
MrOS study, the mean BMD was 5.9% lower at the spine
and 3.9% at the proximal hip in men using SSRIs than in
those using other antidepressants or no medications.11
This difference in BMD persisted even after adjusting for
the known potential confounders and, interestingly, the
BMD deficit was of similar magnitude to that induced by
glucocorticoids.11 Furthermore, in the Study of Osteoporotic
Fractures, women using SSRIs had 1.7-fold greater annual
declines in hip BMD than those using either no antidepressants or else tricyclic antidepressants (0.82% vs. 0.47%; P
< 0.001).12 In addition, a recent study reported lower BMD
in children and adolescents receiving SSRIs.13 Collectively,
these data strongly suggest that SSRIs reduce BMD, accelerate age-related bone loss, and raise fracture risk in all age
groups and in both genders.
Conclusions
Evidence is growing that depression itself and treatment with SSRIs are both associated with reduced bone
mass accumulation during growth, accelerated bone loss
in older adults, and increased risk of fractures in both men
and women. The widespread use of SSRIs to treat depres-
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Endocrine NewsUIFUPQJDTBVUIPSTBOEPVUTJEF
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[email protected].
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BSUJDMFTPOBWBSJFUZPGUPQJDTQFSUBJOJOHUPFOEPDSJOPMPHZSFTFBSDIBOEQSBDUJDFQMFBTFWJTJUUIFEndocrine
News 8FCTJUFXXXFOEPTPDJFUZPSHFOEP@OFXTBOE
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sion and as an alternative therapy for hot flashes may put
a large number of people at higher risk for low BMD and
fractures. Further studies are needed to understand fully
the impact of both depression and its treatment on the
skeleton. Although a direct causal relationship between
SSRIs and fractures has not been rigorously established,
it is prudent to use SSRIs carefully in individuals at high
risk for osteoporosis. Q
References:
Clinical Researcher
1. Haney EM, Chan BK, Diem S, et al. Association of low bone mineral density with selective serotonin reuptake inhibitor use by older
men. Arch Intern Med, 2007;167:1246–1251.
2. Richards JB, Papaioannou A, Adachi JD, et al. Canadian Multicentre Osteoporosis Study Research Group. Effect of selective
serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med,
2007;167:188–194.
3. Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressants and
rates of hip bone loss in older women: The study of osteoporotic
fractures. Arch Intern Med, 2007;167:1240–1245.
4. Vestergaard P, Rejnmark L, Mosekilde L. Anxiolytics, sedatives,
antidepressants, neuroleptics and the risk of fracture. Osteoporos Int,
2006;17:807–816.
5. Bolton JM, Metge C, Lix L, Prior H, Sareen J, Leslie WD. Fracture
risk from psychotropic medications: A population-based analysis. J
Clin Psychopharmacol, 2008;28:384–391.
6. Liu B, Anderson G, Mittmann N, To T, Axcell T, Shear N. Use
of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet,
1998;351(9112):1303–1307.
7. Haney EM, Parimi N, Diem SJ, et al. SSRI use is associated with
increased risk of fracture among older men. J Bone Miner Res,
2007;22:s45.
8. Ziere G, Dieleman JP, van der Cammen TJ, Hofman A, Pols HA,
Stricker BH. Selective serotonin reuptake inhibiting antidepressants
are associated with an increased risk of nonvertebral fractures. J Clin
Psychopharmacol, 2008;28:411–417.
9. Spangler L, Scholes D, Brunner RL, et al. Depressive symptoms,
bone loss, and fractures in postmenopausal women. J Gen Intern Med,
2008;23:567–574.
10. Hubbard R, Farrington P, Smith C, Smeeth L, Tattersfield A.
Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture. Am J Epidemiol,
2003;158:77–84.
Basic Researcher
1. Haney EM, Chan BKS, Diem SJ, et al. Association of low bone
mineral density with selective serotonin reuptake inhibitor use by
older men. Arch Intern Med, 2007;167:1246–1251.
2. Laekeman G, Zwaenepoel L, Reyntens J, de Vos M, Casteels M.
Osteoporosis after combined use of a neuroleptic and antidepressants. Pharm World Sci, 2008;30:613–616.
2007;167:188–194.
4. Yadav VK, Oury F, Suda N, et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and
energy expenditure. Cell, 2009;138:976–989.
5. Oury F, Yadav VK, Wang Y, et al. CREB mediates brain serotonin
regulation of bone mass through its expression in ventromedial
hypothalamic neurons. Genes Dev, 2010;24:2330–2342.
6. Yadav VK, Oury F, Tanaka K, et al. Leptin-dependent serotonin
control of appetite: Temporal specificity, transcriptional regulation,
and therapeutic implications. J Exp Med, 2011;208:41–52.
7. Mann JJ, McBride PA, Brown RP, et al. Relationship between central
and peripheral serotonin indexes in depressed and suicidal psychiatric inpatients. Arch Gen Psychiatry, 1992;49:442–446.
Clinical Practitioner
1. Mazziotti G, Canalis E, Giustina A. Drug-induced osteoporosis:
Mechanisms and clinical implications. Am J Med, 2010;123:877–
884.
2. Bliziotes M. Update in serotonin and bone. J Clin Endocrinol Metab,
2010;95:4124–4132.
3. Liu B, Anderson G, Mittmann N, To T, Axcell T, Shear N. Use
of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet,
1998;351(9112):1303–1307.
2007;167:188–194.
5. Warden SJ, Nelson IR, Fuchs RK, Bliziotes MM, Turner CH. Serotonin (5-hydroxytryptamine) transporter inhibition causes bone
loss in adult mice independently of estrogen deficiency. Menopause,
2008;15:1176–1183.
6. Spangler L, Scholes D, Brunner RL, et al. Depressive symptoms,
bone loss, and fractures in postmenopausal women. J Gen Intern Med,
2008;23:567–574.
7. Whooley MA, Kip KE, Cauley JA, Ensrud KE, Nevitt MC,
Browner WS. Depression, falls, and risk of fracture in older women.
Study of Osteoporotic Fractures Research Group. Arch Intern
Med,1999;159:484–490.
8. Schweiger U, Deuschle M, Körner A, et al. Low lumbar bone
mineral density in patients with major depression. Am J Psychiatry,
1994;151:1691–1693.
9. Ford DE, Erlinger TP. Depression and C-Reactive protein in US
adults: Data from the Third National Health and Nutrition Examination Survey. Arch Intern Med, 2004;164:1010–1014.
10. Ding C, Parameswaran V, Udayan R, Burgess J, Jones G. Circulating levels of inflammatory markers predict change in bone mineral
density and resorption in older adults: A longitudinal study. J Clin
Endocrinol Metab, 2008;93(5):1952–1958.
11. Haney EM, Chan BK, Diem SJ, et al. Association of low bone
mineral density with selective serotonin reuptake inhibitor use by
older men. Arch Intern Med, 2007;167:1246–1251.
12. Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressants and
rates of hip bone loss in older women: The study of osteoporotic
fractures. Arch Intern Med, 2007;167:1240–1245.
13. Calarge CA, Zimmerman B, Xie D, Kuperman S, Schlechte JA. A
cross-sectional evaluation of the effect of risperidone and selective
serotonin reuptake inhibitors on bone mineral density in boys. J
Clin Psychiatry, 2010;71:338–347.
For additional links related to this feature, please visit
Endocrine News Online at www.endo-society.org/endo_news.
About This Series
27
Innovative Research
Combined with a Tradition of Care
The Montefiore Einstein Diabetes Center, the home of a Diabetes Research Center,
has been funded by the National Institutes of Health for over 30 years and is a leader
in basic and translational research that examines the causes of diabetes in the hope of
finding more effective treatments. With a collaborative infrastructure and multiple tools
to facilitate diabetes prevention and control, we support broad interplay among research,
training, clinical care and community-based activities.
t%FTJHOBUFEBTB%JBCFUFT$FOUFSPG
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For more information log on to www.montefiore.org or call 866-MED-TALK (633-8255).
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Hospital are recognized among the top
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FEATURE
Focuson
Fibroids
By Margie Patlak*
3
32
News. Also commenting was molecular biologist Julie
Kim, Ph.D., of Northwestern University in Evanston, Ill.
“I’m sure if you were to ask a woman whether she would
prefer to take a pill for the treatment of fibroids or have
surgery, the pill would win hands down.”
Rising to meet that demand for medical therapy is a
cadre of committed researchers who are rapidly uncovering the molecular mechanisms behind uterine fibroids.
Their research has turned up numerous drug targets,
some of which are currently being tested in the clinic.
“There has been an exponential increase recently in the
number of publications on the topic,” Dr. Al-Hendy noted.
The research has revealed the importance of progesterone
in fostering fibroids and has teased apart some of the
molecular threads in the extensive web of overactive cell
signaling. This altered signaling results in the tangled
mess of collagen and other fibers in uterine cells that is
the hallmark of fibroids.
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T
hree-quarters of women develop uterine fibroids
in their lifetime, and as many as one-fourth
suffer from them. Yet what causes these common
outcroppings in the womb has largely remained a
mystery. That is unfortunate, given that the excessive
bleeding, pain, constipation, and difficulty urinating
caused by these noncancerous tumors prompt nearly
200,000 women in the United States each year to have
hysterectomies—and risk infection, adhesions, and
damage to nearby organs. For women not done bearing
children, hysterectomies are obviously not an option.
“For women a generation or so ago, hysterectomy was
acceptable because they had completed their families at a
younger age. But times have changed and women tend to
delay starting a family, so there’s a demand for nonsurgical
alternatives,” gynecologist Ayman Al-Hendy, M.D, Ph.D.,
who directs the Center for Women’s Health Research at
Meharry Medical College in Nashville, Tenn., told Endocrine
33
33
Steroid Suspects
Experts have suspected for a while that steroid hormones
play an important role in uterine fibroids, given that the
longer a woman menstruates, the greater the likelihood
she’ll develop fibroids and that they often diminish in size
and symptoms once a woman hits menopause. Although a
lot of the blame for fibroids in the past has been heaped on
estradiol, recent findings suggest it should not bear the brunt
of the blame—estradiol acts as the trigger, but progesterone
plays the predominant role in fostering uterine leiomyomas.
Estradiol is required for fibroid cells to sprout progesterone
receptors, studies show, but both the progesterone derivative
P4 and estradiol are needed to prompt fibroid growth—neither hormone will by itself do this. When both hormones are
withdrawn, fibroids shrink in size. These findings are bolstered
by the clinical observation that the growth of these tumors
is stimulated in postmenopausal women by hormone therapy
that includes progestin, but no boost in growth occurs when
only supplemental estrogens are taken.
Acting Locally
Circulating levels of both estradiol and progesterone
are similar in women with or without fibroids, suggesting
that it’s all about location. Studies support this notion,
finding more up-regulation of estrogen and progesterone
receptors in uterine fibroids than in normal myometrium,
as well as greater amounts of estradiol in fibroids, whose
cells can produce the hormone.
The burning question is what is churning up this localized
production of steroid hormones and their receptors? Some evidence suggests that for select women, the heightened hormonal
environment in their wombs is due to too much aromatase,
which converts testosterone to estrogens. Studies also find
that certain variants of the estradiol-metabolizing enzyme
catechol-O-methyltransferase (COMT) can shift the balance so
more active estrogen metabolites are produced locally. Growth
factors, such as insulin-like growth factor-I (IGF-I), may also
be responsible in part, although it’s hard to tell which comes
first. For example, IGF-I can indirectly activate estrogen receptor _, but estrogens can also up-regulate IGF-I expression. As
Dr. Kim summed up, “It’s more complex than the amount of
circulating or local hormones.” Dr. Al-Hendy added, “These
tumors seem to be self-sustaining—they produce their own
steroids and probably many other growth factors as well.”
Crosstalk Chatter
34
The complexity becomes apparent when you consider all the
chemical chatting estradiol and progesterone do with a number
of growth factors known to promote growth and inhibit cell
death, including platelet-derived growth factor (PDGF), transforming growth factor (TGF), epidermal growth factor (EGF),
vascular endothelial growth factor (VEGF), and IGF-I. A large
and diverse group of these compounds is apparently needed to
support fibroids. A study found that 39 of 42 of the scrutinized
tyrosine kinase receptors necessary for activating growth factors were expressed in human uterine fibroid tissues more than
in normal myometrium tissue. One of the implicated growth
factors, TGF`, is especially known for promoting the growth
of the collagen fiber tendrils that make up the bulk of these
growths, whereas others specialize in promoting the growth of
blood vessel cells that are probably needed to support fibroids,
and might contribute to the excessive bleeding they cause.
Although the sheer number of growth factors involved can
be overwhelming, only some make especially desirable therapeutic targets. As Dr. Kim pointed out, “A lot of these growth
factors have common pathways, and it’s really the pathways
that are dictating what goes on, in terms of a physiological
response.” Some of the same molecular pathways active in
tumor growth, such as the notorious PI3K/AKT and its affiliated mTOR pathway, are also overly active in uterine fibroids.
Dr. Kim noted, however, that unlike for malignant tumors,
many growth-regulating pathways are still likely to be operational in fibroids. It is thus possible that relatively minor
molecular tweaking may be all that’s needed to limit their
growth. For that tweaking, Dr. Al-Hendy suggested focusing
on a few master checkpoints or regulators of the molecular
pathways involved in these growths, most notably progesterone receptor, mTOR, aromatase, and COMT.
Hitting Hormones
Anti-fibroid compounds that are furthest along in the
testing process are selective progesterone receptor modulators (SPRMs). Several have been tested in clinical trials, and
these compounds have reduced related symptoms such as
bleeding and/or uterine fibroid volume. Despite these promising results, one SPRM called asoprisnil caused endometrial
changes similar to, but not exactly the same as, hyperplasia.
The concern that asoprisnil might precipitate cancer led one
company to discontinue its phase II testing of this SPRM, but
clinical testing of others continues in women with fibroids.
In contrast, selective estrogen receptor modulators
(SERMs) such as raloxifene have not proven exceptionally
effective in stemming fibroid growth. There’s some hope
that aromatase inhibitors, e.g., letrozole or anastrozole,
might reduce estrogen production enough to shrink these
tumors, but not enough to cause bone problems or hot
flashes. Pilot studies have found that aromatase inhibitors
can decrease fibroid size and symptoms.
Clinical studies have shown that the progesterone receptor antagonist RU486 (mifepristone) also reduces fibroid
volume and symptoms, but this drug is currently approved
only for abortion. The doses for this use are much higher
than daily doses to reduce fibroids in these clinical studies.
Apparently daily fibroid treatment is needed, because the
masses returned when treatment stopped.
Intriguingly, progestin-releasing intrauterine devices
have been reported by some researchers to significantly
reduce uterine fibroid symptoms in some women, although
other findings conflict. Some experts speculate that such
localized release of progestin might stem fibroids by curbing the expression of endometrial progesterone receptors
in the uterus. Researchers also report that low-dose birth
control pills can help stem the heavy bleeding experienced
by some women with this condition.
Natural Agents
Compounds currently being tested for reducing uterine
fibroids include natural compounds that target TGF or COMT.
These include vitamin D3 and such nutritional stars as resveratrol, which is found in grape skins, and EGCG, the anti-oxidant
found in green tea. A recent in vitro study revealed that resveratrol not only inhibited cell proliferation and induced human
fibroid cell death in vitro, it also reduced the production of
two types of collagen in a dose-dependent manner, apparently
by blocking the action of TGF`. Gregory M. Christman, M.D.,
reported the unpublished study last year at “Advances in
Uterine Leiomyoma Research: 3rd NIH International Congress.”
Dr. Al-Hendy showed in animal and in vitro studies that
both vitamin D3 and EGCG inhibit proliferation of fibroid cells
by affecting COMT, which ultimately caused progesterone
receptor levels to drop. A pilot clinical trial of EGCG is under
way and another is planned for vitamin D3 in subjects with
uterine fibroids, according to Dr. Al-Hendy. “I’m very excited
about this new direction, because these compounds are well
tolerated with little to no side effects, so we can entertain
the concept of using them for fibroid prevention,” he said.
This paradigm shift in thinking about prevention is possible,
Dr. Al-Hendy pointed out, now that he has found, and Donna
Baird, Ph.D., at the University of North Carolina at Chapel Hill
has confirmed in a larger study, that insufficient serum vitamin
D3 is a risk factor for fibroids. These researchers found that the
lower the serum vitamin D3 levels in women with symptomatic
fibroids, the greater their tumor burden. Interestingly, vitamin
D deficiency is 10 times more prevalent in African Americans
than in other populations and may explain why they experience uterine fibroids much more than Caucasians. According
to Dr. Al-Hendy, it’s conceivable that vitamin D supplements
taken regularly might prevent fibroids in some women, if not
relieve their burden once it has become established.
Hope is palpable that preventives and treatments will soon
develop from the flurry of current research in fibroids, and those
therapies surely will be welcomed by the millions of women
plagued by the condition. As Elizabeth Stewart, M.D., of the
Mayo Clinic in Rochester, Minn., pointed out at the 2010 NIH
fibroids meeting, “Fibroids cause significant impairment of
health for millions of women—[having fibroids] affects them
during the years when they have the most demands on their
time, both from raising families and establishing careers.”
With scientists on the charge, although fibroids may
still claim a lot of victims, their days are numbered. Q
* Margie Patlak is a free-lance science writer, living in the Philadelphia area.
Resources:
t Kim JJ, Sefton EC. The role of progesterone signaling in the pathogenesis of uterine leiomyoma. Mol Cell Endocrinol, 2011, doi:10.1016/j.
mce.2011.05.044.
t Zhang D, Al-Hendy M, Richard-Davis G, et al. Green tea extract inhibits proliferation of uterine leiomyoma cells in vitro and in nude mice.
American Journal of Obstetrics and Gynecology, 2010, March;202(3):289.
t Halder SK, Goodwin JS, Al-Hendy A. 1,25-dihydroxyvitamin D3
reduces TGF-Beta3-induced fibrosis-related gene expression in human
uterine leiomyoma. J Clin Endocrinol Metab, April 2011;96(4):E754–E762.
t More links at www.endo-society.org/endo_news.
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:WLJPHSWYLMLYLUJLMVYmore than 400 awards and grants
www.endo-society.org/renew
© 2011 The Endocrine Society®
Introducing
a smart
partnership
For patients not at goal
on insulin glargine, adding
BYETTA® can deliver a
complementary approach
to glycemic control
Indication and usage
BYETTA is indicated as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes mellitus.
❍ Not a substitute for insulin and should not be used in
patients with type 1 diabetes or diabetic ketoacidosis.
❍ Concurrent use with prandial insulin cannot be recommended.
❍ Has not been studied in patients with a history of pancreatitis.
It is unknown whether patients with a history of pancreatitis
are at increased risk for pancreatitis while using BYETTA;
consider other antidiabetic therapies for these patients.
❍
❍
Contraindications
❍
BYETTA is contraindicated in patients with prior severe
hypersensitivity reactions to exenatide or to any of the
product components.
❍
❍
Warnings and precautions
❍
Based on postmarketing data BYETTA has been
associated with acute pancreatitis, including fatal and
non-fatal hemorrhagic or necrotizing pancreatitis. After
initiation and dose increases of BYETTA, observe patients
carefully for pancreatitis (persistent severe abdominal
pain, sometimes radiating to the back, with or without
vomiting). If pancreatitis is suspected, BYETTA should be
❍
discontinued promptly. BYETTA should not be restarted if
pancreatitis is confirmed.
Increased risk of hypoglycemia when used in combination with
glucose-independent insulin secretagogues (eg, sulfonylureas);
reduction of the sulfonylurea dose may be needed. When used
with insulin, evaluate and consider reducing the insulin dose in
patients at increased risk of hypoglycemia.
Postmarketing reports of altered renal function, including
increased serum creatinine, renal impairment, worsened
chronic renal failure, and acute renal failure, sometimes
requiring hemodialysis and kidney transplantation. BYETTA
should not be used in patients with severe renal impairment
or end-stage renal disease. Use with caution in patients with
renal transplantation or when initiating or escalating the
dose in patients with moderate renal failure.
Not recommended in patients with severe gastrointestinal
disease (eg, gastroparesis).
Patients may develop antibodies to exenatide. In 3 registration
trials, antibody levels were measured in 90% of patients, with up
to 4% of patients having high-titer antibodies and attenuated
glycemic response. If worsening of or failure to achieve adequate
glycemic control occurs, consider alternative antidiabetic therapy.
Postmarketing reports of serious hypersensitivity reactions
(eg, anaphylaxis and angioedema). If this occurs, patients should
discontinue BYETTA and other suspect medications and
promptly seek medical advice.
BYETTA added to titrated insulin glargine achieved a significantly greater A1C reduction vs titrated insulin glargine alone
Mean change in A1C at 30 weeks
LS mean change in A1C (%)
0
(BL = 8.3)
(n = 137)
-0.4
-1.0 %
-0.8
-1.2
-1.6
(BL = 8.5)
(n = 122)
Patients with type 2 diabetes on insulin glargine alone or in combination with oral
agents (metformin, thiazolidinedione, or both) were enrolled in a 30-week,
randomized, double-blind, placebo-controlled clinical study to receive either BYETTA
(5 mcg BID for 4 weeks then 10 mcg BID) or placebo in addition to titrated insulin
glargine. In both arms, under investigator guidance, insulin was titrated to achieve a
targeted fasting glucose level of <100 mg/dL using the Treat-to-Target algorithm.
❍
-1.7%
-2.0
BYETTA plus titrated insulin glargine (n = 137)
Titrated insulin glargine alone (n = 122)
P < .01 vs titrated insulin glargine alone.
ITT population.
BYETTA did not increase the risk of hypoglycemia over that
seen with insulin glargine alone and provided the potential
benefit of weight loss (on average, 4.0 lb over 30 weeks).*
Consider reducing the dose of insulin glargine in patients at
increased risk for hypoglycemia.
*BYETTA is not indicated for the management of obesity, and
weight change was a secondary endpoint.
Abbreviations: LS, least squares; BL, baseline; ITT, intent to treat.
Warnings and precautions (cont‘d)
Drug interactions
❍
❍
No clinical studies establishing conclusive evidence of macrovascular
risk reduction with BYETTA or any other antidiabetic drug.
Adverse reactions
❍
❍
❍
Most common adverse reactions in registration trials associated
with BYETTA vs placebo (PBO): nausea (44% vs 18%),
vomiting (13% vs 4%), and diarrhea (13% vs 6%). Other
adverse reactions ≥5% and more than PBO: feeling jittery,
dizziness, headache, and dyspepsia. With a thiazolidinedione
(TZD), adverse reactions were similar; as monotherapy, most
common was nausea (8% vs 0%). With insulin glargine: nausea
(41% vs 8%), vomiting (18% vs 4%), diarrhea (18% vs 8%),
headache (14% vs 4%), constipation (10% vs 2%), dyspepsia
(7% vs 2%), asthenia (5% vs 1%).
Hypoglycemia incidence, BYETTA vs PBO, with metformin
(MET): 5.3% (10 mcg) and 4.5% (5 mcg) vs 5.3%; with SFU,
35.7% (10 mcg) and 14.4% (5 mcg) vs 3.3%; with MET + SFU,
27.8% (10 mcg) and 19.2% (5 mcg) vs 12.6%; with TZD, 10.7%
(10 mcg) vs 7.1%; as monotherapy, 3.8% (10 mcg) and 5.2%
(5 mcg) vs 1.3%; with insulin glargine, 24.8% (10 mcg) vs
29.5%.
Withdrawals: as monotherapy, 2 of 155 BYETTA patients
withdrew due to headache and nausea vs 0 PBO; with MET and/
or SFU vs PBO, nausea (3% vs <1%) and vomiting (1% vs 0);
with TZD ± MET, nausea (9%) and vomiting (5%), with <1% of
PBO patients withdrawing due to nausea; with insulin glargine
vs PBO, nausea (5.1% vs 0), vomiting (2.9% vs 0).
❍
BYETTA slows gastric emptying and can reduce the extent and
rate of absorption of orally administered drugs. Use with caution
with medications that have a narrow therapeutic index or
require rapid gastrointestinal absorption. Medications dependent
on threshold concentrations for efficacy should be taken at least
1 hour before BYETTA.
Postmarketing reports of increased international normalized ratio
(INR) sometimes associated with bleeding with concomitant use
of warfarin. Monitor INR frequently until stable upon initiation or
alteration of BYETTA.
Use in specific populations
❍
❍
❍
Based on animal data, BYETTA may cause fetal harm and should
be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Caution should be exercised when administered to a nursing woman.
Safety and effectiveness have not been established in pediatric patients.
To learn more, visit www.ByettaHCP.com.
For additional safety profile and other important
prescribing considerations, please see the adjacent pages
for Brief Summary of Prescribing Information.
ET
BY
TA® HAS
A
Over 6 years on the market
Over 1 million patients†
Over 8.5 years of clinical experience
P
RO
02-11-12444-A ©2011 AMYLIN PHARMACEUTICALS, INC. AND LILLY USA, LLC.
PRINTED IN USA. ALL RIGHTS RESERVED.
The BYETTA mark and BYETTA design mark are registered trademarks of Amylin Pharmaceuticals, Inc.
†
VE N
H I ST
OR
Y
SDI data, December 2009.
BYETTA® (exenatide) injection
Brief Summary: For complete details, please see full Prescribing Information.
Type 2 Diabetes Mellitus
BYETTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with
type 2 diabetes mellitus.
Important Limitations of Use
BYETTA is not a substitute for insulin. BYETTA should not be used for the treatment of type
1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.
The concurrent use of BYETTA with prandial insulin has not been studied and cannot be
recommended.
Based on postmarketing data BYETTA has been associated with acute pancreatitis, including fatal
and non-fatal hemorrhagic or necrotizing pancreatitis. BYETTA has not been studied in patients with a
history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk
for pancreatitis while using BYETTA. Other antidiabetic therapies should be considered in patients with
a history of pancreatitis.
DOSAGE AND ADMINISTRATION
Recommended Dosing
Inject subcutaneously within 60 minutes prior to morning and evening meals (or before the two
main meals of the day, approximately 6 hours or more apart). Initiate at 5 mcg per dose twice daily;
increase to 10 mcg twice daily after 1 month based on clinical response. Do not mix with insulin. Do not
transfer BYETTA from the pen to a syringe or vial.
CONTRAINDICATIONS
Hypersensitivity
BYETTA is contraindicated in patients with prior severe hypersensitivity reactions to exenatide or to
any of the product components.
Acute Pancreatitis
Based on postmarketing data BYETTA has been associated with acute pancreatitis, including
fatal and non-fatal hemorrhagic or necrotizing pancreatitis. After initiation of BYETTA, and after
dose increases, observe patients carefully for signs and symptoms of pancreatitis (including
persistent severe abdominal pain, sometimes radiating to the back, which may or may not be
accompanied by vomiting). If pancreatitis is suspected, BYETTA should promptly be discontinued
and appropriate management should be initiated. If pancreatitis is confirmed, BYETTA should
not be restarted. Consider antidiabetic therapies other than BYETTA in patients with a history of
pancreatitis.
Use with Medications Known to Cause Hypoglycemia
The risk of hypoglycemia is increased when BYETTA is used in combination with a sulfonylurea.
Therefore, patients receiving BYETTA and a sulfonylurea may require a lower dose of the sulfonylurea to
reduce the risk of hypoglycemia.
When BYETTA is used in combination with insulin, the dose of insulin should be evaluated. In
patients at increased risk of hypoglycemia consider reducing the dose of insulin. The concurrent use
of BYETTA with prandial insulin has not been studied and cannot be recommended. It is also possible
that the use of BYETTA with other glucose-independent insulin secretagogues (e.g. meglitinides) could
increase the risk of hypoglycemia.
Renal Impairment
BYETTA should not be used in patients with severe renal impairment (creatinine clearance
< 30 mL/min) or end-stage renal disease and should be used with caution in patients with renal
transplantation. In patients with end-stage renal disease receiving dialysis, single doses of BYETTA 5 mcg
were not well-tolerated due to gastrointestinal side effects. Because BYETTA may induce nausea and
vomiting with transient hypovolemia, treatment may worsen renal function. Caution should be applied
when initiating or escalating doses of BYETTA from 5 mcg to 10 mcg in patients with moderate renal
impairment (creatinine clearance 30 to 50 mL/min).
There have been postmarketing reports of altered renal function, including increased serum
creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring
hemodialysis or kidney transplantation. Some of these events occurred in patients receiving one or more
pharmacologic agents known to affect renal function or hydration status, such as angiotensin converting
enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or diuretics. Some events occurred in patients
who had been experiencing nausea, vomiting, or diarrhea, with or without dehydration. Reversibility of
altered renal function has been observed in many cases with supportive treatment and discontinuation of
potentially causative agents, including BYETTA. Exenatide has not been found to be directly nephrotoxic
in preclinical or clinical studies.
Gastrointestinal Disease
BYETTA has not been studied in patients with severe gastrointestinal disease, including
gastroparesis. Because BYETTA is commonly associated with gastrointestinal adverse reactions,
including nausea, vomiting, and diarrhea, the use of BYETTA is not recommended in patients with severe
gastrointestinal disease.
Immunogenicity
Patients may develop antibodies to exenatide following treatment with BYETTA. Antibody levels
were measured in 90% of subjects in the 30-week, 24-week and 16-week studies of BYETTA. In 3%, 4%
and 1% of these patients, respectively, antibody formation was associated with an attenuated glycemic
response. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative
antidiabetic therapy should be considered.
Hypersensitivity
There have been postmarketing reports of serious hypersensitivity reactions (e.g. anaphylaxis and
angioedema) in patients treated with BYETTA. If a hypersensitivity reaction occurs, the patient should
discontinue BYETTA and other suspect medications and promptly seek medical advice.
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk
reduction with BYETTA or any other antidiabetic drug.
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
Hypoglycemia
Table 1: Incidence (%) and Rate of Hypoglycemia When BYETTA was Used as Monotherapy or With
Concomitant Antidiabetic Therapy in Six Placebo-Controlled Clinical Trials*
BYETTA
Placebo twice daily
5 mcg twice daily
10 mcg twice daily
Monotherapy (24 Weeks)
N
77
77
78
% Overall
1.3%
5.2%
3.8%
Rate (episodes/patient-year)
0.03
0.21
0.52
% Severe
0.0%
0.0%
0.0%
With Metformin (30 Weeks)
N
113
110
113
% Overall
5.3%
4.5%
5.3%
0.12
0.13
0.12
% Severe
0.0%
0.0%
0.0%
With a Sulfonylurea (30 Weeks)
N
123
125
129
% Overall
3.3%
14.4%
35.7%
0.07
0.64
1.61
% Severe
0.0%
0.0%
0.0%
With Metformin and a Sulfonylurea (30 Weeks)
N
247
245
241
% Overall
12.6%
19.2%
27.8%
0.58
0.78
1.71
% Severe
0.0%
0.4%
0.0%
With a Thiazolidinedione (16 Weeks)
N
112
not evaluated
121
% Overall
7.1%
not evaluated
10.7%
Rate (episodes/patient-years)
0.56
not evaluated
0.98
% Severe
0.0%
not evaluated
0.0%
With Insulin Glargine (30 Weeks) †
N
122
not evaluated
137
% Overall
29.5%
not evaluated
24.8%
Rate (episodes/patient-years)
1.58
not evaluated
1.61
% Severe
0.8%
not evaluated
0.0%
* A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without
a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event
with symptoms consistent with hypoglycemia requiring the assistance of another person and associated
with either a blood glucose value consistent with hypoglycemia or prompt recovery after treatment for
hypoglycemia.
†
When BYETTA was initiated in combination with insulin glargine, the dose of insulin glargine was
decreased by 20% in patients with an HbA1c ≤ 8.0 % to minimize the risk of hypoglycemia. See Table 9
for insulin dose titration algorithm.
N = The number of Intent-to-Treat subjects in each treatment group.
Immunogenicity
Antibodies were assessed in 90% of subjects in the 30-week, 24-week and 16-week studies of
BYETTA. In the 30-week controlled trials of BYETTA add-on to metformin and/or sulfonylurea, antibodies
were assessed at 2- to 6-week intervals. The mean antibody titer peaked at week 6 and was reduced by
55% by week 30. Three hundred and sixty patients (38%) had low titer antibodies (<625) to exenatide
at 30 weeks. The level of glycemic control (HbA1c) in these patients was generally comparable to that
observed in the 534 patients (56%) without antibody titers. An additional 59 patients (6%) had higher titer
antibodies (≥625) at 30 weeks. Of these patients, 32 (3% overall) had an attenuated glycemic response
to BYETTA; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without
antibodies.
In the 16-week trial of BYETTA add-on to thiazolidinediones, with or without metformin, 36 patients
(31%) had low titer antibodies to exenatide at 16 weeks. The level of glycemic control in these
patients was generally comparable to that observed in the 69 patients (60%) without antibody titer. An
additional 10 patients (9%) had higher titer antibodies at 16 weeks. Of these patients, 4 (4% overall)
had an attenuated glycemic response to BYETTA; the remaining 6 (5% overall) had a glycemic response
comparable to that of patients without antibodies.
In the 24-week trial of BYETTA used as monotherapy, 40 patients (28%) had low titer antibodies to
exenatide at 24 weeks. The level of glycemic control in these patients was generally comparable to that
observed in the 101 patients (70%) without antibody titers. An additional 3 patients (2%) had higher titer
antibodies at 24 weeks. Of these patients, 1 (1% overall) had an attenuated glycemic response to BYETTA;
the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies.
Antibodies to exenatide were not assessed in the 30-week trial of BYETTA used in combination
with insulin glargine.
Two hundred and ten patients with antibodies to exenatide in the BYETTA clinical trials were tested
for the presence of cross-reactive antibodies to GLP-1 and/or glucagon. No treatment-emergent cross
reactive antibodies were observed across the range of titers.
Other Adverse Reactions
Monotherapy
Adverse reactions (excluding hypoglycemia) for the 24-week placebo-controlled study of BYETTA
BID (N = 155) when used as a monotherapy, with an incidence ≥2% and occurring more frequently in
BYETTA-treated patients versus placebo BID-treated patients (N = 77): nausea (8% vs 0%), vomiting (4%
vs 0%), and dyspepsia (3% vs 0%).
Adverse reactions reported in ≥1.0 to <2.0% of patients receiving BYETTA and reported more
frequently than with placebo included decreased appetite, diarrhea, and dizziness. The most frequently
reported adverse reaction associated with BYETTA, nausea, occurred in a dose-dependent fashion.
Two of the 155 patients treated with BYETTA withdrew due to adverse reactions of headache and
nausea. No placebo-treated patients withdrew due to adverse reactions.
Combination Therapy
Add-on to metformin and/or sulfonylurea
Adverse reactions (excluding hypoglycemia) in the three 30-week controlled trials of BYETTA BID
(N = 963) add-on to metformin and/or sulfonylurea, with an incidence ≥2% and occurring more frequently
in BYETTA-treated patients versus placebo-treated patients (N = 483): nausea (44% vs 18%), vomiting
(13% vs 4%), diarrhea (13% vs 6%), feeling jittery (9% vs 4%), dizziness (9% vs 6%), headache (9%
vs 6%), dyspepsia (6% vs 3%), asthenia (4% vs 2%), gastroesophageal reflux disease (3% vs 1%), and
hyperhydrosis (3% vs 1%).
frequently than with placebo included decreased appetite. Nausea was the most frequently reported
adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and
severity decreased over time in most of the patients who initially experienced nausea. Patients in the longterm uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions
than those observed in the 30-week controlled trials.
The most common adverse reactions leading to withdrawal for BYETTA-treated patients were
nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew due to nausea
and none due to vomiting.
Add-on to thiazolidinedione with or without metformin
BID (N = 121) add-on to a thiazolidinedione, with or without metformin, with an incidence ≥2% and
occurring more frequently in BYETTA-treated patients versus placebo-treated patients (N = 112): nausea
(40% vs 15%), vomiting (13% vs 1%), dyspepsia (7% vs 1%), diarrhea (6% vs 3%), and gastroesophageal
refiux disease (3% vs 0%).
frequently than with placebo included decreased appetite. Chills (n = 4) and injection-site reactions
(n = 2) occurred only in BYETTA-treated patients. The two patients who reported an injection-site
reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic
hypersensitivity pneumonitis) were reported in the BYETTA arm. No serious adverse events were reported
in the placebo arm.
The most common adverse reactions leading to withdrawal for BYETTA-treated patients were
nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to nausea.
Add-on to insulin glargine with or without metformin and/or thiazolidinedione
BID (N = 137) as add-on to insulin glargine with or without oral antihyperglycemic medications with an
incidence ≥2% and occurring more frequently in BYETTA-treated patients versus placebo-treated patients
(N = 122): nausea (41% vs 8%), vomiting (18% vs 4%), diarrhea (18% vs 8%), headache (14% vs 4%),
constipation (10% vs 2%), dyspepsia (7% vs 2%), asthenia (5% vs 1%), abdominal distention (4% vs 1%),
decreased appetite (3% vs 0%), flatulence (2% vs 1%), gastroesophageal reflux disease (2% vs 1%).
The most frequently reported adverse reactions leading to withdrawal for BYETTA-treated patients
were nausea (5.1%) and vomiting (2.9%). No placebo-treated patients withdrew due to nausea or
vomiting.
Post-Marketing Experience
The following additional adverse reactions have been reported during post-approval use of BYETTA.
Because these events are reported voluntarily from a population of uncertain size, it is generally not
possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular or
papular rash, angioedema, anaphylactic reaction.
Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use
sometimes associated with bleeding.
Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension,
abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing
pancreatitis sometimes resulting in death.
Neurologic: dysgeusia; somnolence
Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal
impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis),
kidney transplant and kidney transplant dysfunction.
Skin and Subcutaneous Tissue Disorders: alopecia
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of BYETTA use in pregnant women. In animal
studies, exenatide caused cleft palate, irregular skeletal ossification and an increased number of neonatal
deaths. BYETTA should be used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
Female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout
mating until gestation day 7 had no adverse fetal effects. At the maximal dose, 760 mcg/kg/day, systemic
exposures were up to 390 times the human exposure resulting from the maximum recommended dose
of 20 mcg/day, based on AUC.
In developmental toxicity studies, pregnant animals received exenatide subcutaneously during
organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or
260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from
exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day,
based on AUC. Moreover, fetuses from pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day
from gestation day 6 through 15 demonstrated reduced fetal and neonatal growth, cleft palate and skeletal
effects at systemic exposure 3 times the human exposure resulting from the maximum recommended
dose of 20 mcg/day, based on AUC.
Lactating mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation
day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were observed on
postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure
resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Pregnancy Registry
Amylin Pharmaceuticals, Inc. maintains a Pregnancy Registry to monitor pregnancy outcomes of women
exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling
1-800-633-9081.
Nursing Mothers
It is not known whether exenatide is excreted in human milk. However, exenatide is present at low
concentrations (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous
dosing) in the milk of lactating mice. Many drugs are excreted in human milk and because of the potential
for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made
whether to discontinue nursing or discontinue the drug, taking into account these potential risks against
the glycemic benefits to the lactating woman. Caution should be exercised when BYETTA is administered
to a nursing woman.
Pediatric Use
Safety and effectiveness of BYETTA have not been established in pediatric patients.
Geriatric Use
Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests
that age does not influence the pharmacokinetic properties of exenatide. BYETTA was studied in 282
patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or
effectiveness were observed between these patients and younger patients. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection in the elderly based
on renal function.
OVERDOSAGE
In a clinical study of BYETTA, three patients with type 2 diabetes each experienced a single
overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses included
severe nausea, severe vomiting, and rapidly declining blood glucose concentrations. One of the three
patients experienced severe hypoglycemia requiring parenteral glucose administration. The three patients
recovered without complication. In the event of overdose, appropriate supportive treatment should be
initiated according to the patient’s clinical signs and symptoms.
Manufactured for Amylin Pharmaceuticals, Inc., San Diego, CA 92121
Marketed by Amylin Pharmaceuticals, Inc. and Eli Lilly and Company
1-800-868-1190
http://www.BYETTA.com
Literature Revised October 2011
BYETTA is a registered trademark of Amylin Pharmaceuticals, Inc.
© 2005, 2011 Amylin Pharmaceuticals, Inc. All rights reserved.
822015-EE
02-09-9300-D
RESEARCH BRIEFS
³ The following studies will be published in Endocrine Society journals.
Before print, they are edited and
posted online, in each journal's Early
Release section. You can access the
journals via www.endo-society.org.
Endocrinology
³ Increased 5-hydroxytryptamine
secretion from activated platelets
is an understudied area of insulin
resistance.
Li Q, Hosaka T, Shikama Y, et al.
Heparin-binding EGF-like growth factor (HB-EGF) mediates 5-HT–induced
insulin.
³ RA controls spermatogonia differentiation through both the somatic and germinal compartments
of the seminiferous epithelium.
Gely-Pernot A, Raverdeau M, Célébi C,
et al. Spermatogonia differentiation
requires retinoic acid receptor gamma.
³ A non-osteoclast source of
tumor growth factor ` drives mesenchymal stem cell recruitment
to support parathyroid hormone’s
anabolic actions.
Koh AJ, Novince CM, Li X, Wang
T, Taichman RS, McCauley LK. An
irradiation-altered bone marrow
microenvironment impacts anabolic
actions of PTH.
40
³ Hypothalamic neurokinin B
neurons are involved in generating menopausal flushes.
Dacks PA, Krajewski SJ, Rance NE.
Activation of neurokinin 3 receptors
in the median preoptic nucleus decreases core temperature in the rat.
³ In atherosclerosis, OSCAR
induces cell activation and inflammation.
Goettsch C, Rauner M, Sinningen
K, et al. The osteoclast-associated
receptor (OSCAR) is a novel receptor
regulated by oxidized low density lipoprotein in human endothelial cells.
The Journal of Clinical
Endocrinology & Metabolism
³ Roux-en-Y gastric bypass patients with the I251L allele, compared with controls, are predisposed to reduced type 2 diabetes
risk and more weight loss.
Mirshahi UL, Still CD, Masker KK,
Gerhard GS, Carey DJ, Mirshahi T.
The MC4R (I251L) allele is associated
with better metabolic status and more
weight loss following gastric bypass
surgery.
³ Kisspeptin-10, which stimulates
gonadotrophin release in women
during the preovulatory phase,
also stimulates its release in men.
Jayasena CN, Nijher GMK, Comninos
AN, et al. The effects of kisspeptin-10
on reproductive hormone release show
sexual dimorphism in humans.
³ In older men who are losing
weight, higher endogenous testosterone is linked to decreased loss
of both lean mass and lower extremity function.
LeBlanc ES, Wang PY, Lee CG, et al.
Higher testosterone levels are associated with less loss of lean body mass
in older men.
³ Activated dendritic cells express
Smad2 and the transforming
growth factor ` signaling pathway.
Both are key factors in diabetogenesis.
Hook SM, Phipps-Green AJ, Faiz F, et
al. Smad2: A candidate gene for the
murine autoimmune diabetes locus
Idd21.1.
incretin hormone–mediated beta cell
proliferation.
³Serum- and glucocorticoidregulated kinase 3 plays a physiological role in `-cell function via
`-catenin.
Yao L-J, McCormick JA, Wang J, et
al. Novel role for SGK3 in glucose
homeostasis revealed in SGK3/Akt2
double-null mice.
³The NFAT1-Stat5 signaling
pathways antagonize each other in
breast cancer, possibly contributing to cancer pathogenesis.
Zheng J, Fang F, Zeng X, et al.
Negative crosstalk between NFAT1 and
Stat5 signaling in breast cancer.
³IGF-I works through GH/GHR
signaling to enhance `-cell mass
and function.
Ma F, Wei Z, Shi C, et al. Signaling
crosstalk between growth hormone
(GH) and insulin-like growth factor-I
(IGF-I) in pancreatic islets `-cells.
DECEMBER 2011 issue of
Endocrine Reviews
³ O’Sullivan ES, Vegas A, Anderson
DG, Weir GC. Islets transplanted in
immunoisolation devices: A review of
the progress and the challenges that
remain.
³ Bartolomucci A, Possenti R,
Mahata SK, et al. The extended
granin family: Structure, function,
and biomedical implications.
Molecular Endocrinology
³ Fiorina P, Voltarelli J, Zavazava N.
Immunological applications of stem
cells in type 1 diabetes.
³Glucoincretins act via the Irs2PI3-kinase signaling pathway to
help degrade the cell cycle inhibitor p27 via the SCF ubiquitin
ligase complex containing Skp2.
Tschen S-I, Georgia S, Dhawan S,
Bhushan A. Skp2 is required for
³ Rivkees SA, Mazzaferri EL,
Verburg FA, et al. The treatment of
differentiated thyroid cancer in children: Emphasis on surgical approach
and radioactive iodine therapy. Q
S POTLIGHT
Government Standards for
Study Participants
In May, the Society1 responded to
a request from the Presidential Commission for the Study of Bioethical
P OLICY
Advocating for Improved
Clinical Research Regulations
By Katie Moore, Ph.D.*
Issues regarding federal and international standards for protecting
the well-being of participants in
scientific studies supported by the
federal government. The comments
reflect concerns about the research
approval process, the difficulties of
recruiting and retaining volunteers
to participate in clinical studies, and
the lack of diversity in U.S. clinical
research studies.
Specifically, the letter suggests
that all institutions interested in
clinical research—including the NIH,
foundations, pharmaceutical companies, and medical centers—would
benefit from working together to
build networks of diverse, community-based practitioners who can help
with candidates for clinical trials. In
addition, the letter urges Congress
and the Food and Drug Administration to adopt guidelines on including women and minority populations
in clinical trials. These recommendations, which are presented in the
Society’s white paper on increasing
minority participation in clinical
research, support Society President
Janet Hall and the Society’s focus on
health disparities in endocrinology.2
Revisions to the Common Rule
In October, the Society submitted
a letter3 commenting on an Advanced
Notice of Proposed Rule Making
(ANPRM), titled “Human Subjects
Research Protections: Enhancing
Protections for Research Subjects and
Reducing Burden, Delay, and Ambiguity for Investigators.” The ANPRM
solicited input from the community
on ways to reduce regulatory burdens
while maintaining high standards of
patient safety.
The Society emphasized the need
to streamline Institutional Review
Board (IRB) review of multi-site
studies, improve survey instruments
and consent forms, and establish
consistency and efficiency among
study reviews. Regarding multi-site
studies, the Society supports use
of centralized IRBs as a means to
advance clinical research and improve patient care while minimizing
regulatory burdens. This concept is
presented more fully in the Society’s
June 2011 Position Statement on
central IRBs 4 and in the Society’s
response to the ANPRM.3
The Society will continue to advocate on behalf of clinical researchers to decrease clinical research
regulatory burdens and ensure that
efforts are made to facilitate clinical research progress through the
streamlining of clinical research
protocol approval and the modernization of research regulations. Q
* Katie Moore, Ph.D., is Manager, Science
Policy, The Endocrine Society.
Resources:
1. www.endo-society.org/advocacy/legislative/
letters/upload/TES-comments-to-presidentialcommission-5-2-11.pdf.
2. www.endo-society.org/advocacy/health_
disparities/upload/Final-Color-White-Paperwith-Endorsers.pdf.
3. www.endo-society.org/advocacy/legislative/
letters/upload/Endocrine-Society-Comments-onCommon-Rule-ANPRM.pdf.
4. www.endo-society.org/advocacy/policy/upload/
Central-IRB-Position-Statement_Final-2.pdf.
C
linical research is critical for
the development of safer and
more effective treatments for a
large spectrum of diseases, including
many endocrine disorders for which
specialized treatments have yet to
be established. However, regulatory
requirements placed on investigators
often lead to substantial setbacks in
research progress. As a result, clinical research activities in the United
States are declining and the number
of investigators in the field is diminishing. In addition, in some cases,
the public trust in clinical trials has
been damaged, leading to problems
in recruiting participants.
The Endocrine Society has focused considerable advocacy effort on
reducing clinical research regulatory
burdens. In the past year, Society
leadership has met with Zeke Emanuel,
M.D., Ph.D., special advisor for health
policy to the White House, with Office
for Human Research Protections officials, and with National Institutes
of Health (NIH) institute directors to
discuss impediments to clinical investigation and the need to streamline
clinical research protocol approval.
The Society views patient safety
as a top priority in both the implementation of clinical studies and in
the practice of patient care. As part
of its advocacy, the Society strongly
supports regulations that protect human research participants, while not
hindering clinical research progress.
Researchers face a complex array
of regulations for domestic studies,
and those involved in international
investigations must also adhere to
the standards of individual host nations, introducing additional layers
of complexity. To resolve some of
these hurdles, the Society recently
responded to two requests from the
Obama Administration for insight on
the clinical research process.
ON
41
Easy to teach1
—Can be used in 6 straightforward steps
Easy to use1
—Only long-acting insulin pen in which dose can be set from 1 to 80 units in 1-unit steps,
dialed both up and down
—Once opened, Lantus® SoloSTAR® can be used for up to 28 days and is not refrigerated
Easy to inject1
—Dose cannot be dialed past the number of units left in the pen
—It is important to keep the injection button pressed all the way in and to slowly count to 10 before
withdrawing the needle from the skin. After a full injection, the number in the dose window will
return to zero. These steps help ensure that the full dose has been delivered
Indications and Usage for Lantus®
Lantus® is a long-acting insulin analog indicated to improve glycemic control in adults and children
(6 years and older) with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Lantus®
should be administered once a day at the same time every day.
Important Limitations of Use: Lantus® is not recommended for the treatment of diabetic ketoacidosis.
Use intravenous short-acting insulin instead.
Important Safety Information for Lantus®
Contraindications
Lantus® is contraindicated in patients hypersensitive to insulin glargine or one of its excipients.
Warnings and Precautions
Monitor blood glucose in all patients treated with insulin. Insulin regimens should be modified cautiously
and only under medical supervision. Changes in insulin strength, manufacturer, type, or method of
administration may result in the need for a change in insulin dose or an adjustment in concomitant oral
antidiabetic treatment.
Do not dilute or mix Lantus® with any other insulin or solution. If mixed or diluted, the solution may
become cloudy, and the onset of action/time to peak effect may be altered in an unpredictable manner.
Do not administer Lantus® via an insulin pump or intravenously because severe hypoglycemia can occur.
Insulin devices and needles must not be shared between patients.
Hypoglycemia is the most common adverse reaction of insulin therapy, including Lantus®, and may be
life-threatening.
Severe life-threatening, generalized allergy, including anaphylaxis, can occur.
A reduction in the Lantus® dose may be required in patients with renal or hepatic impairment.
Drug Interactions
Certain drugs may affect glucose metabolism, requiring insulin dose adjustment and close monitoring
of blood glucose. The signs of hypoglycemia may be reduced in patients taking anti-adrenergic drugs
(e.g., beta-blockers, clonidine, guanethidine, and reserpine).
Adverse Reactions
Other adverse reactions commonly associated with Lantus® are injection site reaction, lipodystrophy,
pruritus, and rash.
for Lantus® SoloSTAR®
Lantus® SoloSTAR® is a disposable prefilled insulin pen. To help ensure an accurate dose each time,
patients should follow all steps in the Instruction Leaflet accompanying the pen; otherwise they may
not get the correct amount of insulin, which may affect their blood glucose.
Please see brief summary of full prescribing information for Lantus ® on the following pages.
References: 1. Data on file, sanofi-aventis U.S. LLC. 2. Lantus Prescribing Information. April 2010.
For patients with diabetes using an insulin vial and syringe
Take aim with the
Lantus SoloSTAR pen
®
®
a
50% more insulin per prescriptionb of Lantus ® SoloSTAR® for the
same co-pay as a vial and syringe on most insurance plans
Prefilled with Lantus ®, the only 24-hour insulin approved
exclusively for use once a day to help patients with
diabetes aim toward glycemic control 2
Scan the QR code with your mobile phone for more
information about Lantus® and Lantus® SoloSTAR®.
Here’s how to get started:
1. Visit 2dscan.com or search for
“ScanLife” in your app store or
text “SCAN” to 43588
2. Follow the prompts to download
the free application
3. Using the application, take a
photo of the QR code through
the ScanLife application
STARring the #1-prescribed insulinc
a The
SoloSTAR® pen is recommended for use with Becton, Dickinson and Company pen needles.
on how prescription is written.
c Based on TRx data from IMS Health, NPATM Monthly database, time period from May 2003 to June 2010.
b Depending
© 2011 sanofi-aventis U.S. LLC
US.GLA.11.02.020
LANTUS®
Rx Only
(insulin glargine [rDNA origin] injection) solution for subcutaneous injection
Brief Summary of Prescribing Information
1. INDICATIONS AND USAGE
LANTUS is indicated to improve glycemic control in adults and children with type 1 diabetes
mellitus and in adults with type 2 diabetes mellitus.
Important Limitations of Use:
LANTUS is not recommended for the treatment of diabetic ketoacidosis. Intravenous
short-acting insulin is the preferred treatment for this condition.
2. DOSAGE AND ADMINISTRATION
2.1 Dosing
LANTUS is a recombinant human insulin analog for once daily subcutaneous administration with
potency that is approximately the same as the potency of human insulin. LANTUS exhibits a
relatively constant glucose-lowering profile over 24 hours that permits once-daily dosing.
LANTUS may be administered at any time during the day. LANTUS should be administered
subcutaneously once a day at the same time every day. The dose of LANTUS must be
individualized based on clinical response. Blood glucose monitoring is essential in all patients
receiving insulin therapy.
Patients adjusting the amount or timing of dosing with LANTUS, should only do so under medical
supervision with appropriate glucose monitoring [see Warnings and Precautions (5.1).]
In patients with type 1 diabetes, LANTUS must be used in regimens with short-acting insulin.
The intended duration of activity of LANTUS is dependent on injection into subcutaneous tissue
[see Clinical pharmacology (12.2) in the full prescribing information]. LANTUS should not be
administered intravenously or via an insulin pump. Intravenous administration of the usual
subcutaneous dose could result in severe hypoglycemia [see Warnings and Precautions (5.3)].
As with all insulins, injection sites should be rotated within the same region (abdomen, thigh,
or deltoid) from one injection to the next to reduce the risk of lipodystrophy [See Adverse
Reactions (6.1)].
In clinical studies, there was no clinically relevant difference in insulin glargine absorption after
abdominal, deltoid, or thigh subcutaneous administration. As for all insulins, the rate of
absorption, and consequently the onset and duration of action, may be affected by exercise and
other variables, such as stress, intercurrent illness, or changes in co-administered drugs or meal
patterns.
2.2 Initiation of LANTUS therapy
The recommended starting dose of LANTUS in patients with type 1 diabetes should be
approximately one-third of the total daily insulin requirements. Short-acting, premeal insulin
should be used to satisfy the remainder of the daily insulin requirements.
The recommended starting dose of LANTUS in patients with type 2 diabetes who are not
currently treated with insulin is 10 units (or 0.2 Units/kg) once daily, which should subsequently
be adjusted to the patient’s needs.
The dose of LANTUS should be adjusted according to blood glucose measurements. The
dosage of LANTUS should be individualized under the supervision of a healthcare provider in
accordance with the needs of the patient.
2.3 Converting to LANTUS from other insulin therapies
If changing from a treatment regimen with an intermediate- or long-acting insulin to a regimen
with LANTUS, the amount and timing of shorter-acting insulins and doses of any oral
anti-diabetic drugs may need to be adjusted.
If transferring patients from once-daily NPH insulin to once-daily LANTUS, the recommended initial LANTUS dose is the same as the dose of NPH that is being discontinued.
If transferring patients from twice-daily NPH insulin to once-daily LANTUS, the recommended initial LANTUS dose is 80% of the total NPH dose that is being discontinued. This
dose reduction will lower the likelihood of hypoglycemia [see Warnings and Precautions
(5.3)].
4. CONTRAINDICATIONS
LANTUS is contraindicated in patients with hypersensitivity to LANTUS or one of its excipients.
5. WARNINGS AND PRECAUTIONS
5.1 Dosage adjustment and monitoring
Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin
regimen should be made cautiously and only under medical supervision.
Changes in insulin strength, manufacturer, type, or method of administration may result in the
need for a change in insulin dose or an adjustment in concomitant oral anti-diabetic treatment.
As with all insulin preparations, the time course of action for LANTUS may vary in different
individuals or at different times in the same individual and is dependent on many conditions,
including the local blood supply, local temperature, and physical activity.
5.2 Administration
Do not administer LANTUS intravenously or via an insulin pump. The intended duration of
activity of LANTUS is dependent on injection into subcutaneous tissue
Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia
[see Warnings and Precautions (5.3)].
Do not dilute or mix LANTUS with any other insulin or solution. If LANTUS is diluted or mixed,
the solution may become cloudy, and the pharmacokinetic or pharmacodynamic profile (e.g.,
onset of action, time to peak effect) of LANTUS and the mixed insulin may be altered in an
unpredictable manner. When LANTUS and regular human insulin were mixed immediately
before injection in dogs, a delayed onset of action and a delayed time to maximum effect for
regular human insulin was observed. The total bioavailability of the mixture was also slightly
decreased compared to separate injections of LANTUS and regular human insulin. The
relevance of these observations in dogs to humans is unknown.
Do not share disposable or reusable insulin devices or needles between patients, because doing
so carries a risk for transmission of blood-borne pathogens.
5.3 Hypoglycemia
Hypoglycemia is the most common adverse reaction of insulin, including LANTUS. The risk of
hypoglycemia increases with intensive glycemic control. Patients must be educated to recognize
and manage hypoglycemia. Severe hypoglycemia can lead to unconsciousness or convulsions
and may result in temporary or permanent impairment of brain function or death. Severe
hypoglycemia requiring the assistance of another person or parenteral glucose infusion or
glucagon administration has been observed in clinical trials with insulin, including trials with
LANTUS.
The timing of hypoglycemia usually reflects the time-action profile of the administered insulin
formulations. Other factors such as changes in food intake (e.g., amount of food or timing of
meals), exercise, and concomitant medications may also alter the risk of hypoglycemia [See
Drug Interactions (7)].
The prolonged effect of subcutaneous LANTUS may delay recovery from hypoglycemia.
Patients being switched from twice daily NPH insulin to once-daily LANTUS should have their
initial LANTUS dose reduced by 20% from the previous total daily NPH dose to reduce the risk
of hypoglycemia [see Dosage and Administration (2.3)].
As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who
may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or
have erratic food intake). The patient’s ability to concentrate and react may be impaired as a
result of hypoglycemia. This may present a risk in situations where these abilities are especially
important, such as driving or operating other machinery.
Early warning symptoms of hypoglycemia may be different or less pronounced under certain
conditions, such as longstanding diabetes, diabetic neuropathy, use of medications such as
beta-blockers, or intensified glycemic control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia.
5.4 Hypersensitivity and allergic reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin
products, including LANTUS.
5.5 Renal impairment
Due to its long duration of action, Lantus is not recommended during periods of rapidly declining
renal function because of the risk for prolonged hypoglycemia.
Although studies have not been performed in patients with diabetes and renal impairment, a
reduction in the LANTUS dose may be required in patients with renal impairment because of
reduced insulin metabolism, similar to observations found with other insulins. [See Clinical
Pharmacology (12.3) in the full prescribing information].
5.6 Hepatic impairment
Due to its long duration of action, Lantus is not recommended during periods of rapidly declining
hepatic function because of the risk for prolonged hypoglycemia.
Although studies have not been performed in patients with diabetes and hepatic impairment, a
reduction in the LANTUS dose may be required in patients with hepatic impairment because of
reduced capacity for gluconeogenesis and reduced insulin metabolism, similar to observations
found with other insulins. [See Clinical Pharmacology (12.3) in the full prescribing information].
5.7 Drug interactions
Some medications may alter insulin requirements and subsequently increase the risk for
hypoglycemia or hyperglycemia [See Drug Interactions (7)].
6. ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere:
Hypoglycemia [See Warnings and Precautions (5.3)]
Hypersensitivity and allergic reactions [See Warnings and Precautions (5.4)]
6.1 Clinical trial experience
Because clinical trials are conducted under widely varying designs, the adverse reaction rates
reported in one clinical trial may not be easily compared to those rates reported in another
clinical trial, and may not reflect the rates actually observed in clinical practice.
The frequencies of treatment-emergent adverse events during LANTUS clinical trials in patients
with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
Table 1: Treatment –emergent adverse events in pooled clinical trials up to 28
weeks duration in adults with type 1 diabetes (adverse events with
frequency ≥ 5%)
Upper respiratory tract infection
Infection
*
LANTUS, %
(n=1257)
NPH, %
(n=1070)
22.4
23.1
9.4
10.3
Accidental injury
5.7
6.4
Headache
5.5
4.7
LANTUS®
(≤56 mg/dL in the 5-year trial) or prompt recovery after oral carbohydrate, intravenous glucose
or glucagon administration.
The rates of severe symptomatic hypoglycemia in the LANTUS clinical trials (see Section 14
for a description of the study designs) were comparable for all treatment regimens (see Tables
5 and 6). In the pediatric phase 3 clinical trial, children and adolescents with type 1 diabetes
had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups
compared to the adult trials with type 1 diabetes. (see Table 5) [See Clinical Studies (14) in the
full prescribing information].
Table 5: Severe Symptomatic Hypoglycemia in Patients with Type 1 Diabetes
Study A
Type 1
Diabetes
Adults 28
weeks
In combination
with regular
insulin
*Body System not Specified
Table 2: Treatment –emergent adverse events in pooled clinical trials up to 1 year
duration in adults with type 2 diabetes (adverse events with frequency ≥ 5%)
LANTUS, %
(n=849)
NPH, %
(n=714)
11.4
13.3
Infection*
10.4
11.6
Retinal vascular disorder
5.8
7.4
Percent
of
patients
(n/total
N)
Study B
Type 1
Diabetes
Adults 28
weeks
In combination
with regular
insulin
Study C
Type 1
Diabetes
Adults 16
weeks
In combination
with insulin
lispro
Study D
Type 1
Diabetes
Pediatrics 26
weeks
In combination
with regular
insulin
LANTUS
NPH
LANTUS
NPH
LANTUS
NPH
LANTUS
NPH
10.6
(31/
292)
15.0
(44/
293)
8.7
(23/
264)
10.4
(28/
270)
6.5
(20/
310)
5.2
(16/
309)
23.0
(40/
174)
28.6
(50/
175)
Table 6: Severe Symptomatic Hypoglycemia in Patients with Type 2 Diabetes
Table 3: Treatment –emergent adverse events in a 5-year trial of adults with type 2
diabetes (adverse events with frequency ≥ 10%)
LANTUS, %
(n=514)
NPH, %
(n=503)
29.0
33.6
Edema peripheral
20.0
22.7
Hypertension
19.6
18.9
Influenza
18.7
19.5
Sinusitis
18.5
17.9
Cataract
18.1
15.9
Bronchitis
15.2
14.1
Arthralgia
14.2
16.1
Pain in extremity
13.0
13.1
12.3
Back pain
12.8
Cough
12.1
7.4
Urinary tract infection
10.7
10.1
Diarrhea
10.7
10.3
Depression
10.5
9.7
Headache
10.3
9.3
Table 4: Treatment –emergent adverse events in a 28-week clinical trial of children
and adolescents with type 1 diabetes (adverse events with frequency ≥ 5%)
LANTUS, %
(n=174)
NPH, %
(n=175)
Infection*
13.8
17.7
13.8
16.0
Pharyngitis
7.5
8.6
Rhinitis
5.2
5.1
Severe Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin,
including LANTUS [See Warnings and Precautions (5.3)]. Tables 5 and 6 summarize the
incidence of severe hypoglycemia in the LANTUS individual clinical trials. Severe symptomatic
hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring
the assistance of another person and associated with either a blood glucose below 50 mg/dL
Study E
Type 2
Diabetes Adults 52
weeks
In combination with
oral agents
Study F
Type 2
Diabetes Adults 28
weeks
In combination with
regular insulin
Study G
Type 2
Diabetes Adults 5
years
In combination with
regular insulin
LANTUS
NPH
LANTUS
NPH
LANTUS
NPH
1.7
(5/289)
1.1
(3/281)
0.4
(1/259)
2.3
(6/259)
7.8
(40/513)
11.9
(60/504)
Percent
of
patients
(n/total
N)
Retinopathy
Retinopathy was evaluated in the LANTUS clinical studies by analysis of reported retinal
adverse events and fundus photography. The numbers of retinal adverse events reported for
LANTUS and NPH insulin treatment groups were similar for patients with type 1 and type 2
diabetes.
LANTUS was compared to NPH insulin in a 5-year randomized clinical trial that evaluated the
progression of retinopathy as assessed with fundus photography using a grading protocol
derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS). Patients had type 2
diabetes (mean age 55 yrs) with no (86%) or mild (14%) retinopathy at baseline. Mean baseline
HbA1c was 8.4%. The primary outcome was progression by 3 or more steps on the ETDRS
scale at study endpoint. Patients with pre-specified post-baseline eye procedures (pan-retinal
photocoagulation for proliferative or severe nonproliferative diabetic retinopathy, local photocoagulation for new vessels, and vitrectomy for diabetic retinopathy) were also considered as
3-step progressors regardless of actual change in ETDRS score from baseline. Retinopathy
graders were blinded to treatment group assignment. The results for the primary endpoint are
shown in Table 7 for both the per-protocol and Intent-to-Treat populations, and indicate similarity
of Lantus to NPH in the progression of diabetic retinopathy as assessed by this outcome.
Table 7. Number (%) of patients with 3 or more step progression on ETDRS scale
at endpoint
Lantus (%)
NPH (%)
Difference*,†
(SE)
95% CI for
difference
Per-protocol
53/374 (14.2%)
57/363 (15.7%)
-2.0% (2.6%)
-7.0% to +3.1%
Intent-toTreat
63/502 (12.5%)
71/487 (14.6%)
- 2.1% (2.1%)
-6.3% to +2.1%
*Difference = Lantus – NPH
†using a generalized linear model (SAS GENMOD) with treatment and baseline HbA1c strata
(cutoff 9.0%) as the classified independent variables, and with binomial distribution and identity
link function
Insulin initiation and intensification of glucose control
Intensification or rapid improvement in glucose control has been associated with a transitory,
reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute
painful peripheral neuropathy. However, long-term glycemic control decreases the risk of
diabetic retinopathy and neuropathy.
Lipodystrophy
Long-term use of insulin, including LANTUS, can cause lipodystrophy at the site of repeated
insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and
lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin
injection or infusion sites within the same region to reduce the risk of lipodystrophy. [See Dosage
and Administration (2.1)].
Weight gain
Weight gain can occur with insulin therapy, including LANTUS, and has been attributed to the
anabolic effects of insulin and the decrease in glucosuria.
Peripheral Edema
Insulin, including LANTUS, may cause sodium retention and edema, particularly if previously
poor metabolic control is improved by intensified insulin therapy.
Allergic Reactions
Local Allergy
As with any insulin therapy, patients taking LANTUS may experience injection site reactions,
including redness, pain, itching, urticaria, edema, and inflammation. In clinical studies in adult
patients, there was a higher incidence of treatment-emergent injection site pain in LANTUStreated patients (2.7%) compared to NPH insulin-treated patients (0.7%). The reports of pain
at the injection site did not result in discontinuation of therapy.
Rotation of the injection site within a given area from one injection to the next may help to reduce
or prevent these reactions. In some instances, these reactions may be related to factors other
than insulin, such as irritants in a skin cleansing agent or poor injection technique. Most minor
reactions to insulin usually resolve in a few days to a few weeks.
Systemic Allergy
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions,
angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including
LANTUS and may be life threatening.
Antibody production
All insulin products can elicit the formation of insulin antibodies. The presence of such insulin
antibodies may increase or decrease the efficacy of insulin and may require adjustment of the
insulin dose. In phase 3 clinical trials of LANTUS, increases in titers of antibodies to insulin were
observed in NPH insulin and insulin glargine treatment groups with similar incidences.
6.2 Postmarketing experience
The following adverse reactions have been identified during post-approval use of LANTUS.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to estimate reliably their frequency or establish a causal relationship to drug
exposure.
Medication errors have been reported in which other insulins, particularly short-acting insulins,
have been accidentally administered instead of LANTUS [See Patient Counseling Information
(17) in the full prescribing information ]. To avoid medication errors between LANTUS and other
insulins, patients should be instructed to always verify the insulin label before each injection.
7. DRUG INTERACTIONS
A number of drugs affect glucose metabolism and may require insulin dose adjustment and
particularly close monitoring.
The following are examples of drugs that may increase the blood-glucose-lowering effect of
insulins including LANTUS and, therefore, increase the susceptibility to hypoglycemia: oral
anti-diabetic products, pramlintide, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, propoxyphene, pentoxifylline, salicylates, somatostatin analogs, and sulfonamide antibiotics.
The following are examples of drugs that may reduce the blood-glucose-lowering effect of
insulins including LANTUS: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents
(e.g., epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), protease
inhibitors and atypical antipsychotic medications (e.g. olanzapine and clozapine).
Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the
blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may
sometimes be followed by hyperglycemia.
LANTUS®
The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs
such as beta-blockers, clonidine, guanethidine, and reserpine.
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C: Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin
glargine was given to female rats before mating, during mating, and throughout pregnancy at
doses up to 0.36 mg/kg/day, which is approximately 7 times the recommended human
subcutaneous starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m2. In rabbits,
doses of 0.072 mg/kg/day, which is approximately 2 times the recommended human subcutaneous starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m2, were administered
during organogenesis. The effects of insulin glargine did not generally differ from those observed
with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters
of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic
development appeared normal.
There are no well-controlled clinical studies of the use of LANTUS in pregnant women. Because
animal reproduction studies are not always predictive of human response, this drug should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is
essential for patients with diabetes or a history of gestational diabetes to maintain good
metabolic control before conception and throughout pregnancy. Insulin requirements may
decrease during the first trimester, generally increase during the second and third trimesters,
and rapidly decline after delivery. Careful monitoring of glucose control is essential in these
patients.
8.3 Nursing Mothers
It is unknown whether insulin glargine is excreted in human milk. Because many drugs, including
human insulin, are excreted in human milk, caution should be exercised when LANTUS is
administered to a nursing woman. Use of LANTUS is compatible with breastfeeding, but women
with diabetes who are lactating may require adjustments of their insulin doses.
8.4 Pediatric Use
The safety and effectiveness of subcutaneous injections of LANTUS have been established in
pediatric patients (age 6 to 15 years) with type 1 diabetes [see Clinical Studies (14) in the full
prescribing information]. LANTUS has not been studied in pediatric patients younger than 6
years of age with type 1 diabetes. LANTUS has not been studied in pediatric patients with type
2 diabetes.
Based on the results of a study in pediatric patients, the dose recommendation when switching
to LANTUS is the same as that described for adults [see Dosage and Administration (2.3) and
Clinical Studies (14) in the full prescribing information]. As in adults, the dosage of LANTUS must
be individualized in pediatric patients based on metabolic needs and frequent monitoring of
blood glucose.
8.5 Geriatric Use
In controlled clinical studies comparing LANTUS to NPH insulin, 593 of 3890 patients (15%) with
type 1 and type 2 diabetes were ≥65 years of age and 80 (2%) patients were ≥75 years of age.
The only difference in safety or effectiveness in the subpopulation of patients ≥65 years of age
compared to the entire study population was a higher incidence of cardiovascular events
typically seen in an older population in both LANTUS and NPH insulin-treated patients.
Nevertheless, caution should be exercised when LANTUS is administered to geriatric patients.
In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage
should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to
recognize in the elderly [See Warnings and Precautions (5.3)].
10. OVERDOSAGE
An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and
sometimes prolonged and life-threatening hypoglycemia. Mild episodes of hypoglycemia can
usually be treated with oral carbohydrates. Adjustments in drug dosage, meal patterns, or
exercise may be needed.
More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be
treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After
apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia.
Rev. April 2010
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
©2010 sanofi-aventis U.S. LLC
GLA-BPLR-SA-APR10
P RACTICE R ESOURCES
Spreading the Word
To help fill these knowledge gaps
and to foster better patient-physician
communication, The Endocrine Society’s Hormone Foundation and the
Oncofertility Consortium teamed up
to create educational tools for men,
women, and the parents of children
with cancer, and for the clinicians who
care for them. Funding from Merck,
Inc., and EMD Serono, Inc., made this
first-of-its-kind multi-media resource,
SaveMyFertility, possible.
Fertility after Cancer: New
Tools for Clinicians and Patients
By Melissa J. Mapes*
“The Hormone Foundation jumped
at the chance to partner with the Oncofertility Consortium,” said Patricia
Green, director of the Foundation, the
Society’s public education affiliate.
“With SaveMyFertility.org, the Foundation can broaden its reach to a new
audience of patients and providers,
giving them much needed tools and
resources, and also raise awareness
about oncofertility nationally. It’s
win-win all round.”
A series of 4 patient fact sheets
in English and Spanish explain in
easy-to-understand terms the risks
of cancer treatment to fertility,
options for fertility preservation,
and management of the long-term
hormonal effects of treatment. Three
pocket guides for physicians outline
treatment risks and fertility preservation options, offer tips for starting
the conversation with patients, and
give referral resources. All are available at SaveMyFertility.org and via
an iPhone app, iSaveFertility (free at
the App Store).
“Close communication is key, not
only for successful treatment, but
for the patient to feel like they are
part of a team,” said A. Musa Zamah,
M.D., Ph.D., reproductive endocrinologist at the University of California,
San Francisco’s Center for Reproductive Health and Center for Reproductive Sciences. He said the oncologist,
reproductive endocrinologist, and
patient need to stay in close contact
to effectively explore the options
and coordinate care.
“The most critical thing for
the patients is to be aware of the
fertility-preservation techniques,”
said Dr. Zamah. Resources like Save
MyFertility.org, MyOncofertility.org,
and FertileHope.org—a subsidiary
of LiveStrong—are great places to
start. Next, patients should consult
a fertility specialist, whether or not
they intend to undergo any preservation treatment. Even if patients
ultimately choose to adopt, employ a
surrogate, or forgo having children,
knowing that they have the ability
to choose is empowering.
During a consultation, doctors
can use the iSaveFertility mobile app
to send fact sheets and a link to a
C
ourtney Bugler had her ovaries
removed at the age of 30. At
32, she gave birth to a healthy
baby boy.
Ms. Bugler was among the first
patients to benefit from the oncofertility program at Northwestern
University in Chicago, Ill. Thanks to
the foresight of her physicians and
her personal determination to bear
a genetically related child, she had
several fertile ova removed and, after
cancer treatment, had an embryo
transfer. “I was a menopausal woman
getting pregnant,” she said. She and
her husband banked 13 more embryos, in case they should decide to
expand their family in the future.
“Cancer patients benefit from
knowing there is life after recovery,”
said Teresa Woodruff, Ph.D., director
of the Oncofertility Consortium at
Northwestern. Speaking about the
future can have “a profoundly positive impact” on morale. For many,
the future means starting a family.
Ms. Bugler said, “Having a child
was very much a part of the quality of life I wanted to have after my
cancer treatment.”
Not all young cancer survivors
are aware of their options for fertility preservation, however, and many
oncologists don’t think they have
the expertise to broach the subject
with their patients. According to a
2009 national survey of physician
practice patterns, less than half
of cancer patients of childbearing
age felt they had been sufficiently
educated about their options for
preserving fertility.
47
P RACTICE R ESOURCES
directory of specialists directly to a
patient’s email, without revealing
the sender’s email address. When
asked why an app makes a good medium, Dr. Woodruff explained that
with the technological revolution
and the up-and-coming generation
of trainees, residents, and fellows,
“Resources packaged with technology are the right way for medicine
to go.” The technology is convenient for clinicians and beneficial to
patients. Instead of feeling overwhelmed with information immediately after the personal crisis of a
cancer diagnosis, patients can refer
at home to resources waiting for
them in their inbox.
Ms. Bugler knows the impact of a
cancer diagnosis and the importance
of having choices. “The greatest
thing that oncofertility treatments
can give patients is options. Espe-
“Close communication
is key, not only for
successful treatment,
but for the patient to
feel like they are part
of a team.”
cially when you are first diagnosed—
it’s at a time when you feel like you
don’t have a ton,” she explained.
As the executive director of the
Young Survival Coalition's Atlanta
affiliate, Ms. Bugler now gives hope
to other men and women working
toward a cancer-free future. Despite
being a pioneer patient in the field
of oncofertility, she and her family
have a normal, healthy life. “My
husband and I say we still got our
happy ending, it just happened 3
years later. The sadness and the pain
and all those things get wiped away
the minute you look at your child.”
Though her son is still a toddler, she
described with laughter how she envisions his teenage years. “One day
when he is 16 and horrible, I can be
like, ‘You have no idea what your
mother did to have you!’ ”
In the years ahead, experts
expect to see live births from cryopreserved ovarian follicles and from
other advanced treatments currently
in the pipeline. But Dr. Woodruff’s
ultimate goal is for the Oncofertility
Consortium to no longer be necessary. “My dream is to get rid of oncofertility altogether. It sounds kind
of funny, but what we need is smart
drugs that target only the cancer
and don’t have the side effects of
infertility.” Q
* Melissa Mapes is a free-lance writer, living in
Washington, D.C.
www.hormone.org
HORMONES & YOU
PLEASE TEAR HERE
Ambiguous Genitalia
Definitions
t Sex chromosomes: the X and Y
chromosomes. Each person usually
has 46 chromosomes, including
two sex chromosomes. Most
females have two X chromosomes
(XX). Most males have one X and
one Y chromosome (XY).
t Sex hormones: chemicals made
by the body that influence sex
development and sexual function,
including estrogen (a female
hormone) and testosterone
(a male hormone).
t Gonads: reproductive organs
(testicles and ovaries). At puberty,
the testicle makes sperm and male
hormones. The ovary releases eggs
and female hormones.
t Genitals: external sex organs, such
as the penis and scrotum in males,
and the clitoris and labia in
females.
t Sex assignment: the sex in which
a child is raised.
t Gender identity: how people think
of themselves—as male or female.
How do the sex organs develop
in the fetus?
Shortly after conception, the gonads
typically develop into either testicles or
EDITORS:
John C. Achermann, MB, MD
Erica A. Eugster, MD
Dorothy I. Shulman, MD
March 2011
ovaries. In males, hormones made by
the testicles then cause the penis and
scrotum to form. In the absence of male
hormones, the female fetus develops a
clitoris, vagina, and labia.
What causes ambiguous genitalia?
There are many different causes of
ambiguous genitalia, which are sometimes grouped according to the sex
chromosomes present.
46, XX DSD occurs when the female
fetus is exposed to excess male hormones
at the time that the genitals are forming.
The most common cause is congenital
adrenal hyperplasia, a condition in which
the adrenal glands (small glands in the
abdomen) overproduce male hormones.
46, XY DSD occurs in the male fetus
when:
t 5IFUFTUJDMFTEPOUEFWFMPQQSPQFSMZ
t 5IFUFTUJDMFTDBOUNBLFFOPVHI
testosterone
t 5IFCPEZDBOUVTFUFTUPTUFSPOF
properly.
Sex chromosome DSD occurs when
there is an atypical number or combination of sex chromosomes. Causes vary
according to the type of variation.
What tests will your child need?
:PVSDIJMETEPDUPSXJMMFYBNJOFZPVS
DIJMEBOEBTLBCPVUZPVSGBNJMZTNFEJDBM
history. The doctor will check your
DIJMETDISPNPTPNFTBOENFBTVSFIPS
mone levels in the blood and possibly
urine. Ultrasound tests and scans can
sometimes show the internal sex organs.
Occasionally, doctors might examine tissue samples from the gonads or look at
them with a special telescope (laparoscope). Sometimes a diagnosis can be
made in a few days; other times it takes
longer.
What factors will be considered in
making a sex assignment for your
child?
You may be faced with a choice of
whether to raise your child as a boy or a
girl. You and your doctor will consider:
t 5IFDBVTFPGZPVSDIJMETDPOEJUJPOJG
the cause can be found) and likely
gender identity
t 5IFBQQFBSBODFPGZPVSDIJMETHFOJUBMT
t 0QUJPOTGPSTVSHFSZ
t )PXXFMMZPVSDIJMETHPOBETBSFMJLFMZ
to function in the future
t 8IFUIFSZPVSDIJMEXJMMCFGFSUJMF
t :PVSGBNJMZTQSFGFSFODFTBOEDVMUVSBM
beliefs.
What is the treatment for
ambiguous genitalia?
The goals of treatment are to ensure
ZPVSDIJMETMPOHUFSNFNPUJPOBMXFMM
being, sexual function, potential for fertility, and a stable gender identity. Treatment
can include hormone therapy (usually at
puberty) and surgery to improve sexual
function and for cosmetic reasons. Doctors
may recommend surgery for some patients
when they are infants. In other cases, parents may choose not to pursue surgery or
to delay it until the child is old enough to
contribute to the decision.
What resources can help with
ambiguous genitalia?
You and your child should see a team
of health care providers, with specialists in
newborn health, genetics, endocrinology
(hormones), pediatric surgery or urology,
and psychology. Many parents and
children have found that support groups
are helpful.
Resources
Find-an-Endocrinologist:
www.hormone.org or call
1-800-HORMONE (1-800-467-6663)
Mayo Clinic information about ambiguous
genitalia: www.mayoclinic.com/health/
ambiguous-genitalia/DS00668
Hormone Foundation information about
CAH (see this link and search for CAH):
www.hormone.org/Resources/factsheets.cfm
Consortium on Disorders of Sex
Development. Handbook for Parents:
http://dsdguidelines.org
For more information on how to find an endocrinologist, download free publications, translate this fact sheet into other languages, or make a
contribution to The Hormone Foundation, visit www.hormone.org or call 1-800-HORMONE (1-800-467-6663). The Hormone Foundation, the
public education affiliate of The Endocrine Society (www.endo-society.org), serves as a resource for the public by promoting the prevention,
treatment, and cure of hormone-related conditions. This page may be reproduced non-commercially by health care professionals and health educators
to share with patients and students.
© The Hormone Foundation 2011
A M B I G U O U S G E N I TA L I A
What does “ambiguous genitalia”
mean?
The term “ambiguous genitalia” means
UIBUBOFXCPSOCBCZTHFOJUBMTMPPLEJGGFS
ent than the genitals of most boys or girls.
Parents and doctors cannot tell right away
XIBUUIFOFXCPSOTTFYJT'PSFYBNQMFB
baby can have an enlarged clitoris that
looks more like a small penis, and fusion of
the labia so that they look more like a
scrotum. In some babies, the penis does
not form or is very small, and the opening
where urine comes out can be at the base
of the penis, not at the tip. Conditions
that have these features are called disorders
of sex development, or DSD.
LAS HORMONAS Y USTED
www.hormone.org
Ó R G A N O S G E N I TA L E S A M B I G U O S
Órganos genitales ambiguos
¿Qué quiere decir ‘órganos genitales
ambiguos’?
El término ‘órganos genitales ambiguos’
significa que los órganos genitales de un
recién nacido se ven diferentes a los de la
mayoría de los niños o niñas. Los padres y
médicos no pueden determinar de inmediato
el sexo del recién nacido. Por ejemplo, un
bebé puede tener un clítoris grande que se
asemeja más a un pene pequeño y fusión de
los labios, por lo que tienen una apariencia
más similar al escroto. En algunos bebés,
el pene no se forma o es muy pequeño, y la
apertura por la cual sale la orina puede estar
en la base del pene en vez de la punta. Las
aflicciones de estas características se denominan trastornos del desarrollo sexual (disorders
of sex development o DSD en inglés).
Definiciones
t Cromosomas sexuales: los
cromosomas X e Y. Generalmente,
las personas tienen 46 cromosomas,
incluidos dos cromosomas sexuales.
La mayoría de las mujeres tiene dos
cromosomas X (XX). La mayoría de
los hombres tiene un cromosoma X y
uno Y (XY).
t Hormonas sexuales: las sustancias
químicas producidas por el cuerpo
pueden tener una influencia en el
desarrollo sexual y la función sexual,
lo que incluye el estrógeno (la
hormona femenina) y testosterona
(la hormona masculina).
t Gónada: órganos reproductivos
(testículos y ovarios). Durante la
pubertad, los testículos producen
esperma y hormonas masculinas.
Los ovarios liberan óvulos y hormonas
femeninas.
t Órganos genitales: los órganos
sexuales externos, como el pene y
el escroto en los hombres, y el clítoris
y los labios en las mujeres.
t Determinación del sexo: el sexo con
el que se cría a un niño.
t Identidad sexual: el concepto que
tienen las personas de si son hombres
o mujeres.
EDITORES:
John C. Achermann, MB, MD
Erica A. Eugster, MD
Dorothy I. Shulman, MD
Marzo del 2011
¿Cómo se desarrollan los órganos
sexuales del feto?
Poco después de la concepción, las gónadas
típicamente se convierten en testículos u ovarios. En los hombres, las hormonas producidas
por los testículos luego hacen que se formen
el pene y escroto. A falta de hormonas masculinas, se desarrollan el clítoris, la vagina y
los labios en el feto femenino.
¿Qué causa los órganos genitales
ambiguos?
Hay muchas causas diferentes para órganos
genitales ambiguos, que a veces se agrupan
según los cromosomas sexuales presentes.
El trastorno con 46 XX se presenta cuando el feto femenino es expuesto a un exceso de
hormonas masculinas en el momento en que
los genitales se están formando. La causa más
común es la hiperplasia suprarrenal congénita,
un trastorno en el que las glándulas suprarrenales (pequeñas glándulas en el abdomen)
producen demasiadas hormonas masculinas.
El trastorno con 46 XY se presenta en
el feto masculino cuando:
t -PTUFTUÓDVMPTOPTFEFTBSSPMMBO
debidamente
t -PTUFTUÓDVMPTOPQVFEFOQSPEVDJS
suficiente testosterona
t &MDVFSQPOPQVFEFVUJMJ[BSMBUFTUPTUFSPOB
debidamente.
Los trastornos de los cromosomas sexuales se presentan cuando hay una combinación
o número atípico de cromosomas sexuales.
Las causas varían según el tipo de variación.
¿Qué pruebas requiere su hijo?
El médico de su hijo lo examinará y preguntará sobre la historia médica de la familia.
El médico le hará pruebas de cromosomas y
determinará el nivel de hormonas en la sangre
y posiblemente la orina. A veces, las ecografías
y tomografías pueden mostrar órganos sexuales
internos. En algunos casos, es posible que
los médicos examinen muestras de tejido de
las gónadas y las examinen con un telescopio
especial (laparoscopio). A veces se puede
llegar a un diagnóstico en cuestión de días;
otras veces, puede tomar más tiempo.
¿Qué factores se tomarán en cuenta
al determinar el sexo de su hijo?
Es posible que tenga que tomar una
decisión sobre criar a su hijo como niño o
niña. Usted y su médico deben tomar en
cuenta:
t -BDBVTBEFMUSBTUPSOPEFTVIJKPTJTF
puede determinar la causa) e identidad
sexual probable
t -BBQBSJFODJBEFMPTØSHBOPTHFOJUBMFT
de su hijo
t 0QDJPOFTRVJSÞSHJDBT
t -BTQSPCBCJMJEBEFTEFRVFMBTHØOBEBT
de su hijo funcionen bien en el futuro
t 4JTVIJKPTFSÈGÏSUJM
t -BTQSFGFSFODJBTZDSFFODJBTDVMUVSBMFT
de su familia.
¿Cuál es el tratamiento para órganos
genitales ambiguos?
Los objetivos del tratamiento son asegurar
el bienestar, funcionamiento sexual, potencial de fertilidad e identidad sexual estable
a largo plazo de su hijo. El tratamiento puede
incluir terapia hormonal (generalmente
durante la pubertad) y cirugía para mejorar
el funcionamiento sexual y por razones cosméticas. Es posible que los médicos
recomienden operar a algunos pacientes
durante la infancia. En otros casos, los padres
pueden optar por no hacerle una intervención o retrasarla hasta que el niño tenga edad
para tomar parte en la decisión.
¿Qué recursos de ayuda sobre
órganos genitales ambiguos existen?
Usted y su hijo deben consultar con
un equipo de proveedores de salud, con
especialistas en salud neonatal, genética,
endocrinología (hormonas), cirugía pediátrica, urología y sicología. Para muchos padres y
niños, los grupos de apoyo han sido útiles.
Recursos
Encuentre a un endocrinólogo:
www.hormone.org o llame a
1-800-467-6663
Información de la Mayo Clinic sobre órganos
genitales ambiguos: www.mayoclinic.com/
health/ambiguous-genitalia/DS00668
Información de la Hormone Foundation
sobre la hiperplasia suprarrenal congénita
(ir a este enlace y realizar una búsqueda
de CAH): www.hormone.org/Resources/
factsheets.cfm
Consortium on Disorders of Sex
Development. Manual para padres:
http://dsdguidelines.org
Para mayor información sobre cómo encontrar un endocrinólogo, obtener publicaciones gratis en Internet, traducir esta hoja de datos a otros idiomas,
o para hacer una contribución a la Fundación de Hormonas, visite a www.hormone.org o llame al 1-800-HORMONE (1-800-467-6663). La Fundación
de Hormonas, la filial de enseñanza pública de la Sociedad de Endocrinología (www.endo-society.org), sirve de recurso al público para promover
la prevención, tratamiento y cura de trastornos hormonales. Se permite la reproducción de esta página para fines no comerciales por profesionales e
instructores médicos que deseen compartirla con sus pacientes y estudiantes.
© La Fundación de Hormonas 2011
Now FDA-approved Extended Dosing Intervals
of 6 or 8 weeks at 120 mg in controlled patients1*
FOR PATIENTS WITH ACROMEGALY
Somatuline® Depot (lanreotide) Injection
has a unique nanotube formulation that facilitates steady
release into the bloodstream over a prolonged period.1,2
START RIGHT by rapidly achieving therapeutic levels
—within 24 hours of first administration3 using a prefilled syringe
STAY RIGHT by maintaining therapeutic
levels for 6 or 8 weeks when administered at 120 mg1*
INDICATION AND IMPORTANT SAFETY INFORMATION
Somatuline Depot (lanreotide) Injection is a somatostatin analog indicated for the long-term treatment of
patients with acromegaly who have had an inadequate response to or cannot be treated with surgery
and/or radiotherapy.
Patients on Somatuline Depot may experience gallstones, decrease in heart rate, and hypo- and/or
hyperglycemia; monitoring is recommended. Anti-diabetic treatment and dosage of coadministered drugs
that decrease heart rate should be adjusted as necessary. Somatuline Depot may decrease the bioavailability
of cyclosporine, requiring adjustments in cyclosporine doses. The most common adverse reactions are
diarrhea, cholelithiasis, abdominal pain, nausea, and injection site reactions.
*After appropriate once-every-4-week dosage is determined, patients who are controlled on Somatuline Depot 60 mg or 90 mg may
be considered for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks. GH and IGF-1 levels should be
obtained 6 weeks after this change in dosing regimen to evaluate persistence of patient response.
“Controlled” is defined as GH ≤ 2.5 ng/mL, normalized IGF-1, and clinical symptoms controlled.
Please see Indication and Important Safety Information on adjacent page.
References: 1. Somatuline Depot (lanreotide) Injection [US prescribing information]. Brisbane, CA:
Ipsen Pharma; 2011. 2. Valéry C et al. Biomimetic organization: Octapeptide self-assembly into
nanotubes of viral capsid-like dimension. Proc Natl Acad Sci U S A. 2003;100(18):10258-10262.
3. Bronstein M et al. Pharmacokinetic profile of lanreotide Autogel in patients with acromegaly
after four deep subcutaneous injections of 60, 90 or 120 mg every 28 days. Clin Endocrinol (Oxf).
2005;63(5):514-519.
Somatuline Depot is manufactured by Ipsen Pharma Biotech (Signes, France)
and distributed in the United States by Tercica, Inc.
©2011 Tercica, Inc., a subsidiary of the Ipsen Group. April 2011. DEP00085
Formula for Control
TABLE 1: ADVERSE REACTIONS AT AN INCIDENCE > 5% LANREOTIDE OVERALL AND OCCURRING AT HIGHER RATE IN DRUG THAN PLACEBO:
PLACEBO-CONTROLLED AND FIXED-DOSE PHASE OF STUDY 1 BY DOSE
Rx ONLY
BRIEF SUMMARY: Please see package insert for full prescribing
information
Initial US Approval: 2007 Latest Revision: March 2011
----------------------- INDICATIONS AND USAGE ----------------------Somatuline Depot (lanreotide) Injection 60 mg, 90, mg and 120 mg is
indicated for the long-term treatment of acromegalic patients who have had
an inadequate response to surgery and/or radiotherapy, or for whom surgery
and/or radiotherapy is not an option.
The goal of treatment in acromegaly is to reduce growth hormone (GH) and
insulin growth factor-1 (IGF-1) levels to normal.
-------------------------CONTRAINDICATIONS ------------------------None
--------------------WARNINGS AND PRECAUTIONS -------------------Cholelithiasis and Gallbladder Sludge
Lanreotide may reduce gallbladder motility and lead to gallstone formation
therefore, patients may need to be monitored periodically [see Adverse
Reactions (6.1), Clinical Pharmacology (12.2)].
Hyperglycemia and Hypoglycemia
Pharmacological studies in animals and humans show that lanreotide, like
somatostatin and other somatostatin analogs, inhibits the secretion of
insulin and glucagon. Hence, patients treated with Somatuline Depot may
experience hypoglycemia or hyperglycemia. Blood glucose levels should be
monitored when lanreotide treatment is initiated, or when the dose is
altered, and antidiabetic treatment should be adjusted accordingly [see
Adverse Reactions (6.1)].
Thyroid Function Abnormalities
Slight decreases in thyroid function have been seen during treatment with
lanreotide in acromegalic patients, though clinical hypothyroidism is rare
(<1%). Thyroid function tests are recommended where clinically indicated.
Cardiovascular Abnormalities
The most common overall cardiac adverse reactions observed in three
pooled Somatuline Depot Cardiac Studies in patients with acromegaly were
sinus bradycardia (12/217, 5.5%), bradycardia (6/217, 2.8%) and
hypertension (12/217, 5.5%) [see Adverse Reactions (6.1)].
In patients without underlying cardiac disease, lanreotide may lead to a
decrease in heart rate without necessarily reaching the threshold of
bradycardia. In patients suffering from cardiac disorders prior to lanreotide
treatment, sinus bradycardia may occur. Care should be taken when
initiating treatment with lanreotide in patients with bradycardia.
Drug Interactions
The pharmacological gastrointestinal effects of Somatuline Depot may
reduce the intestinal absorption of concomitant drugs.
Lanreotide may decrease the relative bioavailability of cyclosporine.
Concomitant administration of Somatuline Depot and cyclosporine may
necessitate the adjustment of cyclosporine dose to maintain therapeutic
levels [see Drug Interactions (7.2)].
Monitoring: Laboratory Tests
Serum GH and IGF-1 levels are useful markers of the disease and the
effectiveness of treatment [see Dosage and Administration (2)].
-------------------------ADVERSE REACTIONS ------------------------Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
Clinical Studies Experience
The data described below reflect exposure to Somatuline Depot in 416
acromegalic patients in seven studies. One study was a fixed-dose
pharmacokinetic study. The other six studies were open-label or extension
studies, one had a placebo controlled run-in period and another had an
active control. The population was mainly Caucasian (329/353, 93%) with a
median age of 53.0 years of age (range 19–84 years). Fifty-four subjects (13%)
were age 66–74 and eighteen subjects (4.3%) were ≥ 75 years of age. Patients
were evenly matched for gender (205 males and 211 females). The median
average monthly dose was 91.2 mg (e.g., 90 mg injected via the deep
subcutaneous route every 4 weeks) over 385 days with a median cumulative
dose of 1290 mg. Of the patients reporting acromegaly severity at baseline
(N=265), serum GH levels were < 10 ng/mL for 69% (183/265) of the
patients and ≥ 10 ng/mL for 31% (82/265) of the patients.
The most commonly reported adverse reactions reported by > 5% of
patients who received Somatuline Depot (N=416) in the overall pooled
safety studies in acromegaly patients were gastrointestinal disorders
(diarrhea, abdominal pain, nausea, constipation, flatulence, vomiting, loose
stools), cholelithiasis and injection site reactions.
Tables 1 and 2 present adverse reaction data from clinical studies with
Somatuline Depot in acromegalic patients. The tables include data from a
single clinical study and pooled data from seven clinical studies.
Adverse Reactions in Parallel Fixed-Dose Phase of Study 1:
The incidence of treatment-emergent adverse reactions for Somatuline
Depot 60 mg, 90 mg, and 120 mg by dose as reported during the first 4
months (fixed-dose phase) of Study 1 [see Clinical Studies (14)], are
provided in Table 1.
In Study 1, the adverse reactions of diarrhea, abdominal pain and flatulence
increased in incidence with increasing dose of Somatuline Depot.
Adverse Reactions in Long-Term Clinical Trials:
Table 2 provides the most common adverse reactions that occurred in 416
acromegalic patients treated with Somatuline Depot in seven studies. The
analysis of safety compares adverse reaction rates of patients at baseline from
the two efficacy studies, to the overall pooled data from seven studies. Patients
Placebo-Controlled
Double-Blind Phase
Weeks 0 to 4
Body System
Preferred Term
Gastrointestinal System
Disorders
Diarrhea
Fixed-Dose Phase
Double-Blind + Single-Blind
Weeks 0 to 20
Placebo
(N=25)
N (%)
Lanreotide
Overall
(N=83)
N (%)
Lanreotide
60 mg
(N=34)
N (%)
Lanreotide
90 mg
(N=36)
N (%)
Lanreotide
120 mg
(N=37)
N (%)
Lanreotide
Overall
(N=107)
N (%)
1 (4%)
30 (36%)
12 (35%)
21 (58%)
27 (73%)
60 (56%)
0
26 (31%)
9 (26%)
15 (42%)
24 (65%)
48 (45%)
1 (4%)
6 (7%)
3 (9%)
6 (17%)
7 (19%)
16 (15%)
0
5 (6%)
0 (0%)
3 (8%)
5 (14%)
8 (7%)
Application Site Disorders
(Injection site mass/pain/reaction/
inflammation)
0 (0%)
5 (6%)
3 (9%)
4 (11%)
8 (22%)
15 (14%)
Liver and Biliary System
Disorders
1 (4%)
3 (4%)
9 (26%)
7 (19%)
4 (11%)
20 (19%)
Abdominal pain
Flatulence
Cholelithiasis
0
2 (2%)
5 (15%)
6 (17%)
3 (8%)
14 (13%)
Heart Rate & Rhythm Disorders
0
8 (10%)
7 (21%)
2 (6%)
5 (14%)
14 (13%)
Bradycardia
0
7 (8%)
6 (18%)
2 (6%)
2 (5%)
10 (9%)
Red Blood Cell Disorders
0
6 (7%)
2 (6%)
5 (14%)
2 (5%)
9 (8%)
Anemia
0
6 (7%)
2 (6%)
5 (14%)
2 (5%)
9 (8%)
3 (12%)
13 (16%)
8 (24%)
9 (25%)
4 (11%)
21 (20%)
0
7 (8%)
3 (9%)
4 (11%)
2 (5%)
Metabolic & Nutritional
Disorders
Weight decrease
A patient is counted only once for each body system and preferred term.
with elevated GH and IGF-1 levels were either naive to somatostatin analog
therapy or had undergone a 3-month washout [see Clinical Studies (14)].
In addition to the adverse reactions listed in Table 2, the following reactions
were also seen:
t4JOVTCSBEZDBSEJBPDDVSSFEJO
PGQBUJFOUTJOUIFQPPMFE4UVEZ
and 2 and in 3% (13) of patients in the overall pooled studies.
t)ZQFSUFOTJPOPDDVSSFEJO
PGQBUJFOUTJOUIFQPPMFE4UVEZBOE
and in 5% (20) of patients in the overall pooled studies.
t"OFNJBPDDVSSFEJO
PGQBUJFOUTJOUIFQPPMFE4UVEZBOEBOE
in 3% (14) of patients in the overall pooled studies.
Gastrointestinal Adverse Reactions
In the pooled clinical studies of Somatuline Depot therapy, a variety of
gastrointestinal reactions occurred, the majority of which were mild to moderate
in severity. One percent of acromegalic patients treated with Somatuline Depot in
the pooled clinical studies discontinued treatment because of gastrointestinal
reactions. Pancreatitis was reported in < 1% of patients.
Gallbladder Adverse Reactions
In clinical studies involving 416 acromegalic patients treated with
Somatuline Depot, cholelithiasis and gallbladder sludge were reported in
20% of the patients. Among 167 acromegalic patients treated with
Somatuline Depot who underwent routine evaluation with gallbladder
ultrasound, 17.4% had gallstones at baseline. New cholelithiasis was
reported in 12.0% of patients. Cholelithiasis may be related to dose or
TABLE 2: ADVERSE REACTIONS AT AN INCIDENCE > 5.0% IN
OVERALL GROUP REPORTED IN CLINICAL STUDIES
Number and Percentage
of Patients
System Organ Class
Studies
1&2
Overall
Pooled Data
(N=170)
(N=416)
N
%
N
%
Patients With Any Adverse
Reactions
157
92
356
86
Gastrointestinal Disorders
Diarrhea
Abdominal pain
Nausea
Constipation
Flatulence
Vomiting
Loose stools
121
81
34
15
9
12
8
16
71
48
20
9
5
7
5
9
235
155
79
46
33
30
28
23
57
37
19
11
8
7
7
6
Hepatobiliary Disorders
Cholelithiasis
General Disorders and
Administration Site
Conditions
(Injection site pain/mass/
induration/nodule/pruritus)
53
31
99
24
45
27
85
20
51
30
91
22
28
17
37
9
17
Musculoskeletal and
Connective Tissue Disorders
Arthralgia
44
26
70
17
10
30
7
Nervous System Disorders
Headache
34
9
20
5
80
30
19
7
Dictionary - MedDRA 7.1
9 (8%)
Dictionary = WHOART.
duration of exposure [see Cholelithiasis and Gallbladder Sludge (5.1)].
Injection Site Reactions
In the pooled clinical studies, injection site pain (4.1%) and injection site
mass (1.7%) were the most frequently reported local adverse drug reactions
that occurred with the administration of Somatuline Depot. In a specific
analysis 20 of 413 patients (4.8%) presented indurations at the injection
site. Injection site adverse reactions were more commonly reported soon
after the start of treatment and were less commonly reported as treatment
continued. Such adverse reactions were usually mild or moderate but did
lead to withdrawal from clinical studies in two subjects.
Glucose Metabolism Adverse Reactions
In the clinical studies in acromegalic patients treated with Somatuline Depot,
adverse reactions of dysglycemia (hypoglycemia, hyperglycemia, diabetes)
were reported by 14% (47/332) of patients and were considered related to
study drug in 7% (24/332) of patients [see Hyperglycemia and
Hypoglycemia (5.2)].
Cardiac Adverse Reactions
In the pooled clinical studies, sinus bradycardia (3.1%) was the most
frequently observed heart rate and rhythm disorder. All other cardiac
adverse drug reactions were observed in < 1% of patients. The relationship
of these events to Somatuline Depot could not be established because many
of these patients had underlying cardiac disease [see Cardiovascular
Abnormalities (5.4)].
A comparative echocardiography study of lanreotide and another somatostatin
analog demonstrated no difference in the development of new or worsening
valvular regurgitation between the two treatments over one year. The
occurrence of clinically significant mitral regurgitation (i.e., moderate or
severe in intensity) or of clinically significant aortic regurgitation (i.e., at least
mild in intensity) was low in both groups of patients throughout the study.
Other Adverse Reactions
For the most commonly occurring adverse reactions in the pooled analysis,
diarrhea, abdominal pain and cholelithiasis, there was no apparent trend for
increasing incidence with age. GI disorders and renal and urinary disorders
were more common in patients with documented hepatic impairment;
however, the incidence of cholelithiasis was similar between groups.
Laboratory investigations of acromegalic patients treated with Somatuline
Depot in clinical studies show that the percentage of patients with putative
antibodies at any time point after treatment is low (<1% to 4% of patients in
specific studies whose antibodies were tested). The antibodies did not
appear to affect the efficacy or safety of Somatuline Depot.
Postmarketing Experience
As adverse reactions experienced post approval use are reported voluntarily
from a population of uncertain size it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.
The profile of reported adverse reactions for Somatuline Depot was
consistent with that observed for treatment-related adverse reactions in the
clinical studies. Those reported most frequently being gastrointestinal
disorders (abdominal pain and diarrhea) and general disorders and
administration site conditions (injection site reactions). Occasional cases of
pancreatitis have also been observed.
-----------------------------OVERDOSAGE ----------------------------If overdose occurs, symptomatic management is indicated. There are no
confirmed postmarketing cases of overdose with lanreotide that were
serious or led to an adverse reaction. Up-to-date information about the
treatment of overdose can often be obtained from the National Poison
Control Center at 1-800-222-1222.
Manufactured by: Ipsen Pharma Biotech, 83870 Signes, France
Distributed by: Tercica Inc., a subsidiary of the Ipsen Group,
Brisbane, CA 94005 USA
TRAINEE CORNER
Dear Trainee:
Did you know that The Endocrine
Society offers young scientists the
opportunity to compete for up to
$400,000 in awards each year? With
more than 16 different award categories for students, fellows, and early
career professionals, the Society places
great importance in supporting the
growth of its trainee members. You can
visit the Society’s Awards and Grants
Web page to review the awards and
fellowships that are currently available. Here are a few that we’d like to
highlight and key dates to remember:
Endocrine Trainee Day
Class of 2012
Nominations are now being accepted
for the Endocrine Trainee Day Class of
2012 travel awards. Endocrine Trainee
Day will take place on Friday, June 22,
as a kickoff to ENDO 2012 for trainees. The full-day workshop, offered to
graduate students, medical students,
postdoctoral fellows, and clinical fellows, comprises 2 parallel tracks designed to give skills, education, and
career-development opportunities. The
Society’s premier faculty lead interactive sessions on topics spanning the
spectrum of endocrinology. Travel award
selection is competitive; awardees will
receive $400 in travel support and complimentary registration to Endocrine
Trainee Day and ENDO 2012. Trainees
who do not receive a travel award but
wish to attend the related workshop
may register beginning on February 1.
Visit www.endo-society.org/awards/
ENDOAwardsGrants/trainee_day.cfm for
more information and to download the
nomination form. The nomination
deadline is February 6.
Abstract Awards and Travel
Grants
Scientists submitting an abstract
for ENDO 2012 should remember to
apply for other award opportunities,
including:
s Clinical Fellows Travel Grants supported by Amgen
s Clinical Fellow Abstract Awards
and Travel Grants supported by
Pfizer, Inc.
s Clinical Research Fellowship
and Mentor Award supported by
Pfizer, Inc.
s The Endocrine Society Outstanding Abstract Awards
s Mara E. Lieberman Memorial
Travel Grants
s Eugenia Rosemberg Travel Awards
Research Fellowship Awards
The Society is now accepting applications for the following Research
Fellowship Awards. Don’t miss out!
s Summer Research Fellowships supported by The Endocrine Society
s Research Fellowship Award supported by Pfizer, Inc.
s Lilly Endocrine Scholars Award
recognizing the contributions of early
career investigators through increased
exposure. Each includes an honorarium.
To learn more, please visit the Awards
and Grants Web site www.endo-society.
org/awards/index.cfm.
Medical Student Achievement
Award
The Society is accepting nominations for the 2011 Medical Student
Achievement Award until December
31. The award is designed for senior
medical school and osteopathic school
students who have shown exceptional
ability and interest in endocrinology. For information, including a list
of participating institutions, please
visit www.endo-society.org/awards/
SocietyAwards/medical_student.
Early Investigators Awards
Look for information on these and
other awards at www.endo-society.
org/awards. For questions, contact
[email protected]. Q
Society members who are beginning
and working toward building their careers
in endocrine research are encouraged to
apply for one of the Early Investigators
Awards supported by Amgen and Pfizer,
Inc. These awards place an emphasis on
Sincerely,
Kirsta Suggs
Manager, Trainee and Minority
Programs
The Endocrine Society
KEY DATES 2012
ENDOCRINE TRAINEE DAY (www.endo-society.org/endo2012/
trainees.cfm)
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ENDO 2012 ABSTRACT SUBMISSIONS (www.call4abstracts.com/endo)
t "CTUSBDU4VCNJTTJPO%FBEMJOF'FCSVBSZ
RESEARCH FELLOWSHIP AWARDS (www.endo-society.org/awards/
research_fellowship)
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CLINICAL ENDOCRINOLOGY IN-TRAINING EXAM
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ENDO 2012 (www.endo-society.org/endo2012) Houston, Tex.
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BOARD REVIEW (www.endo-society.org) Miami, Fla.
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Apply for an Award!
53
Red Hot Science
is the highlight of ENDO 2012
Submit your best science for presentation in an oral or poster
session at The Endocrine Society’s 94th Annual Meeting & Expo,
June 23–26, 2012, Houston, Texas (ENDO 2012).
ENDO is the premier event to showcase your research. In 2011,
more than 2,600 abstract presenters chose ENDO as the venue to share
their research, exchange ideas, and network with nearly 8,000 endocrine
researchers and practitioners.
Abstract Submission Deadline: February 6, 2012
To submit an abstract or register, visit
www.endo-society.org/endo2012
n
io g
t
n
t ra u s i n !
s
gi Ho pe
e
R nd O
a ow
N
THE clinical endocrinology meeting for endocrinologists and allied
health professionals working in endocrinology, diabetes, and
metabolism. At the Clinical Endocrinology Update (CEU) and Endocrine
Board Review, you’ll have the opportunity to:
Consult with renowned clinicians on the difficult cases you’re
confronted with in your practice
Network with peers to share questions and challenges
Prepare for certification or recertification AND earn CME credit
For meeting updates, visit www.endo-society.org/ceu
Expert Advice for
Today’s Clinical Challenges
ENDOCRINE
2012 Laureate
Award Winners
Gerald D. Aurbach Award Lecture
Evan Dale Abel, M.B.B.S., D.Phil.
The Endocrine Society’s Laureate
awards are presented in recognition
of extraordinary achievements in the field
of endocrinology.
Award recipients
are innovators,
leaders, educators, and practitioners whose
dedication and
accomplishments
are unmatched.
The Society is
pleased to announce the
2012 Laureate Award winners and
congratulate each on their accomplishments. Presentation of the
awards will take place at ENDO 2012
in Houston, Tex. Results are:
Roy O. Greep Award Lecture
Carol A. Lange, Ph.D.
Fred Conrad Koch Award
Samuel Refetoff, M.D.
Robert H. Williams Distinguished
Leadership Award
Leonard Wartofsky, M.D., M.P.H.,
M.A.C.P.
Sidney H. Ingbar Distinguished
Service Award
Alvin M. Matsumoto, M.D., F.A.C.P.
Distinguished Educator Award
Francis S. Greenspan, M.D., Clinical
Professor Emeritus
Distinguished Physician Award
John A. H. Wass, M.A., M.D., F.R.C.P.
Edwin B. Astwood Award Lecture
Keith R. Yamamoto, Ph.D.
Clinical Investigator Award Lecture
Gerald I. Shulman, M.D., Ph.D.
The Endocrine Legacy
The Endocrine Legacy captures
nearly a century of developments
and groundbreaking achievements in
endocrinology, and is free to all Society members. The Endocrine Legacy
includes the complete archive—back
to volume 1, issue 1—of 4 seminal
Society journals: The Journal of
Clinical Endocrinology & Metabolism,
Molecular Endocrinology, Endocrinology, and Endocrine Reviews.
For more information on this essential member benefit, visit www.endosociety.org/legacy or contact Society
Services at societyservices@endo-society.
org or 301-941-0210 (888-363-6762 tollfree in the United States). Q
Ernst Oppenheimer Award
Tamas L. Horvath, D.V.M., Ph.D.
Richard E. Weitzman Memorial Award
Manuel Tena-Sempere, M.D., Ph.D.
For more information about these
prestigious awards, please see www.
endo-society.org/awards/Laureate
Awards/index.cfm.
Patient Guide on
Glucose Monitoring
The Hormone Foundation’s new
Patient Guide to Continuous Glucose
Monitoring is a companion piece
to the Society’s clinical practice
guideline on the same topic. The
guide explains the two main uses
of a continuous glucose monitoring (CGM) system: short-term use
by patients with type 1 or type 2
diabetes to help clinicians make
needed treatment adjustments, and
“real time,” long-term use to help
type 1 patients manage their diabetes day to day. The guide describes
how the sensor, transmitter, and
monitor work and explains the need
for blood glucose testing several
times daily to calibrate the system.
It presents the pros and cons of
CGM and recommends who should
and should not use the device. See
www.hormone.org.
calendar
APR 19–21: NEW ORLEANS, LA.
American College of PhysiciansInternal Medicine 2012
http://im2012.acponline.org/
APR 21–25: SAN DIEGO, CALIF.
Experimental Biology
www.experimentalbiology.org
APR 28–MAY 1: BOSTON, MASS.
Pediatric Endocrinology
www.pas-meeting.org
MAY 5–9: FLORENCE, ITALY
International Congress of Endocrinology (ICE)/European Congress
of Endcrinology (ECE) 2012
www.ice-ece2012.com
MAY 5–9: SAN DIEGO, CALIF.
American College of Obstetricians and
Gynecologists (ACOG) Annual Meeting
www.acog.org/acm
JUN 23–26, 2012: HOUSTON, TEX.
ENDO 2012: The Endocrine Society’s
94th Annual Meeting & Expo.
www.endo-society.org.
SEP 11–15, 2012: MIAMI, FLA.
Board Review and Clinical
Endocrinology Update
www.endo-society.org/ceu
The above events are Endocrine Society–
sponsored. See more events at www.endosociety.org, on the Worldwide Endocrine
Events Calendar.
em
or
iam
M
In
John D. Baxter, M.D.
1940–2011
By the Baxter family*
56
6
John D. Baxter, M.D., worldrenowned scientist and medical
visionary, famous for cloning of
the first human growth hormone
gene, passed away on Wednesday,
October 5, 2011, after an intensive
2-month battle with a rare form of
cancer. He was 71.
Dr. Baxter, former President of
The Endocrine Society (2002–2003),
was previously professor of medicine,
chief of medical endocrinology,
and founder of the University of
California, San Francisco (UCSF)
Diabetes Center. He was most
recently chief of endocrinology at
Methodist Hospital in Houston, Tex.
Dr. Baxter made many
fundamental medical discoveries
and translated them into clinical
therapies that had far-reaching
implications for the fields of
biotechnology and genetic
engineering, and that improved
the health and welfare of patients
worldwide. His laboratory was an
pioneer
early pion
nee in molecular
biology and
recombinant DNA
d re
technology, aand was first to clone
many important
importaant genes, including
those for rat, hu
human, and bovine
growth hormo
hormone.
one His group was
first to show
that growth hormone
w ttha
could be prod
produced
duc in bacteria.
Such “biosynt
“biosynthetic”
human growth
the
hormone is no
now
ow used worldwide
to treat human
humaan growth disorders,
and biosynthe
biosynthetic
eti bovine growth
ussed globally to improve
hormone is used
ion This work became
milk producti
production.
the prototypee fo
for all DNA-based
therap
peu
human therapeutics
and led to
t h l i now used throughout
technologies
the biotechnology industry and
academic research laboratories.
As a scientific entrepreneur,
Dr. Baxter had few equals in the
earliest days of the life sciences
and biotechnology industries,
founding several companies to
facilitate moving his discoveries to
patients. He was the founder and
director of four successful biotech
companies, starting with California
Biotechnology Inc. in 1982, later
acquired by Johnson & Johnson
for $2.4 billion. Dr. Baxter led Cal
Bio’s efforts in developing peptides
for heart failure treatment, as well
as fibroblast growth factors for
wound healing. He also founded
Karo-Bio, AB, in 1987, raising $50
million in initial financing for the
startup, the largest initial amount
of seed funding for any biotech
company in history. Karo-Bio
continues Dr. Baxter’s work and
passion for compounds to help
treat obesity, cholesterol disorders,
and diabetes. In 1991, he founded
SciClone Pharmaceuticals, Inc., now
a publicly traded company that has
a drug in phase III clinical trials in
the United States.
Dr. Baxter, a native of Lexington,
Ky., graduated from Lafayette High
School in 1958, the University of
Kentucky in 1962, and Yale Medical
School with highest honors in
1966. He was a research associate
with the National Institutes of
Health between 1968 and 1970,
then spent nearly 3 decades at UCSF
teaching and conducting research
before taking over as one of the top
researchers at Methodist Hospital.
Dr. Baxter authored more than
245 peer-reviewed scientific articles,
more than 109 books, book chapters
and reviews, and was a member of
more than 10 scientific and medical
societies, including the National
Academy of Sciences, the Institute
of Medicine, and The Endocrine
Society. He received distinguished
service awards from the American
Society of Clinical Investigation, The
Endocrine Society, Yale University,
and the Academy of Medicine,
Engineering and Sciences of Texas.
He also received an honorary
doctorate from the Karolinska
Institute in Stockholm, Sweden,
and the Koch Award, The Endocrine
Society’s highest honor.
Dr. Baxter’s greatest passions he
reserved for the love of his family:
his wife the Hon. Lee D. Baxter, San
Francisco Superior Court (ret.), his
daughters Gillian Galligan and Leslie
Baxter, son-in-law Oliver Galligan,
and grandson Connor.
A giant of a man in stature, life,
and body, Dr. Baxter will surely
by missed by family, friends, and
colleagues who knew and loved him,
and by the hundreds of thousands
of others whose lives were affected
by his gifts here on earth. Q
* This is a condensed version of the full obituary, to be found at www.endo-society.org/obituaries.
“John approached his
leadership of the Society with
energy, passion, and vision.
He saw opportunities for the
Society that boldly opened new
doors in science and medicine.”
— Scott Hunt, Executive Director
and CEO, The Endocrine Society
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57
FEATURE
Preserving our Heritage
A Campaign for the Clark T. Sawin Memorial Library & Resource Center
CONFIDENTIAL PLEDGE FORM
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State
Zip
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To support the priorities of the Campaign to Endow The Clark T. Sawin Memorial Library & Resource Center and to promote an
increased understanding and appreciation of the history of endocrinology in the United States and around the world, I (we) pledge
.
the sum of $
Please list my (our) name(s) in all Reports and on the Wall of
My (our) pledge will be playable in installments of
over the next
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years,
Honor in the appropriate Giving Circle as:
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beginning
on the following schedule (check one):
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Your personal gift is tax deductible to the extent provided by federal and state law. Other forms of gifts can be made, such as appreciated securities
or a bequest. Please contact Amy Woodward, Manager, Development at 301-951-2619 to discuss giving opportunities.
THANK YOU!!
C LASSIFIEDS
Endocrinologist
Multi-specialty group seeks BE/
BC Endocrinologist to join established
practice in a congenial setting. Opportunity to do clinical research if
desired. Look into why more than
400 providers in 27 specialties have
selected MultiCare as their practice
of choice. Recognized as one of the
top 100 health systems in the nation
and the employer of choice in the
community, this physician-driven
organization serves patients in over
16 community sites and four hospitals. You’ll live the Northwest lifestyle
and experience the best of Northwest
living, from big city amenities to
the pristine beauty and recreational
opportunities of the great outdoors.
Apply online at www.careers.blazenew
trails.org, email CV to blazenewtrails@
If you are interested in submitting classified advertising to
Endocrine News, please contact Christine Whorton at
[email protected] or 800-361-3906.
multicare.org or fax your CV to 866264-2818. Visit us on your mobile
device at m.blazenewtrails.org.
Endocrinology Opportunities,
Southern Illinois University
School of Medicine, Springfield,
Illinois
The Department of Internal
Medicine, Division of Endocrinology at Southern Illinois University
seeks two additional Endocrinologists. Both senior and junior faculty
positions are available. Interested
candidates should be board certified
in Internal Medicine, and be board
certified/eligible in Endocrinology.
Southern Illinois University School
of Medicine has a well-established
Endocrinology Fellowship program.
In these positions you will be
involved with patient care and the
teaching of fellows, residents, and
medical students. A faculty appointment is available at the Assistant
or Associate Professor Level based
upon experience and track record.
Opportunities for basic and clinical
research are available based upon
individual interests. Positions offer a
competitive salary, along with a full
and comprehensive benefits package
(including five weeks of vacation,
CME and 11 state holidays). The SIU
School of Medicine values a racially
and culturally diverse workforce.
Southern Illinois University is an
affirmative action/equal opportunity employer. To learn more,
contact Beth Briggs at 800-678-7858
x64454 or [email protected].
ID#139880A15. Q
EXPLORE
NEW HORIZONS
Discover Beebe Medical Center, a progressive,
210-bed, not-for-profit community hospital, located just
six blocks from the Atlantic Coast in Lewes, Delaware.
Here you can pursue an active, challenging medical
career—and enjoy an exceptional quality of life.
ENDOCRINOLOGY OPPORTUNITY AT BEEBE!
Q One of 100 Best Places to Work in Healthcare (Becker’s ASC Review/Becker’s Hospital Review)
Q 2010 & 2011 HealthGrades® Distinguished Hospital Award For Clinical Excellence™
Q 300+ providers on staff; 50,000+ Emergency visits
Q Cardiac surgery, interventional cardiology, cancer center with radiation,
256-slice CT, 3.0T MRI, and PET Scan
OTHER OPPORTUNITIES:
Q Endocrinology Q ENT Q Family Practice Q General/Vascular Surgery
Q Hospitalists (IM) Q Internal Medicine Q OB/GYN Q Pediatrics
Q Orthopaedic Surgery Q Pulmonology/CC/Sleep Q Rheumatology
424 Savannah Road l Lewes, DE 19958 l 302-645-3664 l beebemed.org
E-mail cover letter and CV to: Marilyn Hill, Director of Physician Services,
[email protected]. No recruiting firms, please.
A Unique and Exciting Academic
Faculty Position Available
The Division of Endocrinology and
Metabolism at The University of Texas
Health Science Center at San Antonio
is seeking full-time and part-time
Endocrinologists at the Assistant or
Associate Professor level to contribute to our growing clinical practice,
research activities, and teaching. This
is an exceptional academic opportunity
for a junior faculty member who is self
motivated and excited about patient
care, teaching, and learning and/or
is ready for research independence.
Candidates with strong interest/expertise in metabolic bone disease, thyroid,
adrenal, and/or pituitary diseases are
encouraged to apply. Opportunities to
do clinical research are available. The
candidate must be BC/BE in Endocrinology & Metabolism. San Antonio is
known for its low cost of living and
rich bicultural heritage. Please send
updated curriculum vitae and names
of three references to: Jan M. Bruder,
M.D., Dept. of Medicine/Endocrinology,
7703 Floyd Curl Dr., MSC 7877, San
Antonio, TX 78229-3900. All faculty
appointments are designated as security-sensitive positions. The University
of Texas Health Science Center at San
Antonio is an Equal Employment Opportunity/Affirmative Action Employer.
59
More for You from
C LASSIFIEDS C ONT .
news
n
ews
s
®
Endocrine News Online has a fresh, new look each
month to bring you even more content. Our expanded
Web site will be updated frequently and carry additional
information you don’t want to miss.
e-Edition:
An interactive PDF with pages you can turn,
carrying links to videos, audios, URLs, and more.
Endocrinology Headline news:
Daily headlines from e-newsletters, including
Endocrine Insider, The Endocrine Society UPDATE,
and Weekly Literature Update.
The Endocrine Society news:
Weekly updates of what is happening at the Society.
The Hormone Foundation news:
Links to the latest patient information about
endocrine disorders.
Go to www.endo-society.org/endo_news or scan this QR
Code with your smartphone’s QR Reader to see the many
new online features, headlines, news briefs, interactive text,
photos, and links, among other enhancements.
60
OCHSNER HEALTH SYSTEM in New Orleans is
searching for an ENDOCRINOLOGIST– DIABETOLOGIST to lead the DESIGN, DEVELOPMENT
and IMPLEMENTATION of a COMPREHENSIVE
DIABETES MELLITUS POPULATION MANAGEMENT AND HEALTH CARE DELIVERY PROGRAM.
The successful candidate for this position will be an
ABIM certified Endocrinologist with extensive diabetes expertise, who will work with and coordinate the
activities of primary care and specialist clinicians and
all other Ochsner healthcare professionals involved in
the care of people with diabetes. The goal will be to
develop a comprehensive patient centered care delivery
model for our large number of patients with and at risk
for diabetes.
The Diabetes Program Leader would be expected
to provide clinical care, participate in diabetes research
and publish results. He or she will also provide diabetes
education for Ochsner endocrine fellows, residents and
medical students, as well as staff healthcare professionals. There will be an academic appointment with the
University of Queensland – Ochsner Medical School.
The Ochsner Health System is comprised of 8 hospi-
Academic Endocrinologists—
South Carolina
Division of Endocrinology, USC School of Medicine
in Columbia and Dorn VA Medical Center are seeking
BC/BE endocrinologists at the assistant or associate
professor rank. Great opportunity for a clinician-educator to build a satisfying academic career focused
on patient care, teaching, and research in a relaxed,
FROOHJLDODWPRVSKHUH,QFRPLQJIDFXOW\ZLOOKDYHÁH[ibility to develop any area of interest. Many prospects
for collaboration within the 27,000-student university
campus. The state capital Columbia is a culturally
diverse, metropolitan city that enjoys a mild climate,
offers top-quality standard of living, and is close to
scenic mountains and beaches. Practicing physicians
and graduating fellows are welcome to apply. We offer
DYHU\FRPSHWLWLYHVDODU\DQGH[FHOOHQWEHQHÀWVSDFNage. EOE/AA. Email CV and/or inquiries to Dr. Rizvi at
[email protected] or call 803-540-1000.
tals and 38 clinics across southeast Louisiana, which sees
over 1.5 million clinic patient visits annually. Ochsner is
a major provider of graduate medical education with 23
ACGME accredited residency and fellowship programs.
Ochsner Hospital is certified in Advanced Inpatient Diabetes Management by JCAHO and has an ADA recognized
diabetes education program. The Ochsner Department
of Endocrinology consists of 7 Endocrinologists and 5
Nurse Practitioners in New Orleans, Baton Rouge and
the Northshore of Lake Pontchartrain. It has an ACGME
accredited Endocrinology fellowship training program.
New Orleans is a cosmopolitan, historic city with a
pleasant climate, unique architecture, multiple medical
schools and academic centers, professional sports
teams, world-class dining and cultural interests, and
world-renowned live entertainment and music.
Please email CV to: ochsnerphysiciancv@gmail.
com. Ref. # AEDNO11 or call 800-488-2240 for
more information. EOE.
Sorry, no J-1 visa opportunities available.
P UZZLER P AGE
Ask Yourself …
2. When in space, astronauts literally stretch out. Decreased pressure on the spine in zero gravity
has caused most space travelers
to date to grow:
a. 0.25–0.50 inches
(0.63–1.27 cm)
b. 0.50–1 inches (1.27–2.54 cm)
c. 1–2 inches (2.54–5.08 cm)
d. 2–3 inches (5.08–7.62 cm)
e. 3–4 inches (7.62–10.16 cm)
3. Get a load of melatonin! Which
animal spends about 80% of its
time sleeping?
a. Brown bat
b. Human baby
c. Opossum
d. Owl monkey
e. Python
4. The stapes or stirrup bone in the
middle ear—the smallest bone in
the human body—is about the
length of:
a. A paperclip
b. A kernal of short-grain rice
c. An upper eyelash
d. A staple
e. A milk tooth incisor
5. The drug minoxidil (Rogaine) was
found to promote hair growth,
but it wasn’t originally intended
to treat that. What was it
designed for?
a. Hypertension
b. Acne
c. Cholesterol lowering
d. Diabetes
e. Triglyceride lowering
6. In 250 AD, how was diabetes
diagnosed?
a. Performing a fasting plasma
glucose test
b. Taking the person horseback
riding
c. Spilling a person’s urine on
the ground to see if it
attracted ants
d. Tasting the urine to see if it
was sweet
e. None of these
7. The thyroid gets its name from
the Greek word for ____?
a. Butterfly
b. Apple
c. Neck
d. Bird
e. Shield
8. Who was the first person in
the world to receive insulin for
diabetes?
a. Elizabeth Hughes Gossett
b. Frederick Banting
c. Leonard Thompson
d. Nicolae Paulescu
e. John James Rickard Macleod
9. In Jodi Picoult’s 2009 novel,
Handle with Care, the character
Willow suffers from what disease?
a. Leukemia
b. Asperger’s syndrome
c. Depression
d. Osteogenesis imperfecta
e. Alcoholism
10. Disney recently introduced a new
character with type 1 diabetes
named “Coco.” What kind of
animal is it?
a. Cockatiel
b. Mouse
c. Lion
d. Gorilla
e. Monkey Q
These trivia questions were compiled by
Endocrine News staff. If you have a fun
question to contribute, please send it to
[email protected]. We’d be happy
to give you credit for any items used.
Peek at the Trivia
Answers Online Now
You can check the answers online
immediately at www.endo-society.
org/endo_news under “Puzzler
Page Answers” or wait until you
receive the January 2012 issue
of Endocrine News.
Trivia Fun at ENDO
If you enjoy trivia questions, you
can attend a live and prize-giving
session at ENDO 2012 in Houston,
Tex. This third ENDO Trivia Cup
challenge will be open to all ENDO
attendees at no charge.
ENDOCRINE.%73s$%#%-"%2
1. Which one of the following famous endocrinologists died of an
endocrine-related disease?
a. Hakaru Hashimoto
b. James Tanner
c. Frederick Banting
d. Thomas Addison
e. Fuller Albright
61

Mood Meds news Meddle Bones

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